Catalysts, ligands and use thereof

ABSTRACT

According to the present invention, there is provided a catalytic complex comprising a metal, one or more ligands and one or more counterions, wherein said one or more ligands include a non-racemic chiral ligand and wherein said one or more counterions include a triflimide counterion. Also provided are methods of making said catalytic complex and processes for producing chiral compounds which involve the use of said catalytic complex. In addition, the present invention provides compounds of the formula (2) as defined herein. The compounds of formula (2) may be useful as ligands in catalytic complexes.

FIELD OF THE INVENTION

This invention relates to catalysts and their use in processes forproducing organic compounds. More particularly, the present inventionrelates to catalysts suitable for use in the asymmetric synthesis ofchiral compounds. The present invention also relates to ligands suitablefor use in such catalysts.

BACKGROUND TO THE INVENTION

The development of catalytic methods for asymmetric synthesis is one ofthe foremost achievements in recent chemistry. At present, many broadlyuseful methods for catalytic asymmetric oxidation and reduction exist;however, far fewer catalytic asymmetric methods for formingcarbon-carbon bonds have been devised. This is not only remarkable inview of the importance of carbon-carbon bond formation in synthesis, butalso reflects the major difficulties and challenges associated withenantioselective versions of these transformations. The development ofasymmetric carbon-carbon bond forming reactions that are new, powerfuland practical is of great importance.

Asymmetric conjugate addition reactions with organometallic reagents areone of the most powerful reactions in chemistry. The use of organozincsand Grignard reagents, readily available from alkylhalides, has madeasymmetric catalytic carbon-carbon bond formation based onorganometallic reagents practical. However, whilst the use oforganozincs and Grignard reagents means that obscure reagents are nolonger required, these reagents are still far from ideal. Organometallicprocedures have been extensively developed, but suffer from a number ofsignificant limitations. For instance, in the synthesis of complexmolecules, functional groups may be present which are incompatible withorganometallic reagents. Even the use of a protecting group strategy,which blocks incompatible reaction sites, is often ineffective, due tothe reactivity of organometallic reagents and the extreme sensitivity ofmany asymmetric procedures. Moreover, the reactivity of organometallicreagents is associated with serious safety issues. Asymmetric proceduresare typically highly sensitive to reaction conditions such that onlyparticular solvents may be used. Asymmetric organometallic additionreactions must be also be performed at cryogenic temperatures (e.g. lessthan −30° C.) for high levels of selectively to be obtained. This is notusually possible in industry and so represents a serious limitation ofthese methods. The aforementioned methods are generally too reactive,too expensive and/or of limited availability.

Particular problems are encountered in the enantioselective synthesis ofall-carbon quaternary centres. The ability to construct quaternarycentres with high levels of enantioselectivity is widely regarded as oneof the most important and challenging goals in asymmetric catalysis.Current approaches to this problem involve transition-metal catalysedasymmetric conjugate addition reactions to trisubstituted Michaelacceptors. However, once again, such techniques rely on the use ofhighly reactive pre-made organometallic reagents that can presentpractical and safety issues. The use of functionalized nucleophiles inthese procedures, essential for providing products ready for furtherelaboration, can also be problematic because of the incompatibility offunctional groups with organometallic reagents.

Maksymowicz et al (Nature Chemistry, 2012, 4, 649-654) describe acatalytic asymmetric conjugate addition process in which carbon-carbonbond formation is achieved using alkenes as alkylmetal equivalents. Thedisclosed process involves the use of a catalytic complex comprising ametal source (e.g. a copper source) and a non-racemic chiral ligand(e.g. a phosphoramidite ligand).

There exists a need in the art for further catalysts for use inprocesses for the asymmetric synthesis of organic compounds. Inparticular, there exists a need in the art for improved catalysts foruse in such processes.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provideda catalytic complex comprising a metal, one or more ligands and one ormore counterions, wherein said one or more ligands include a non-racemicchiral ligand and wherein said one or more counterions include atriflimide counterion.

In other aspects, the present invention relates to processes forproducing chiral compounds in a stereoisomeric excess, which processesinvolve the use of the present catalytic complexes. In embodiments, thechiral compounds are produced via a 1,4-conjugate addition reaction or a1,6-conjugate addition reaction. Methods of producing the catalyticcomplexes of the invention are also provided.

The use of a triflimide anion as a counterion may result in enhancedstereoselectivity and provide for an increased stereoisomeric excess inasymmetric reactions, particularly in asymmetric conjugate additionreactions. Thus, the present complexes may allow for the production ofchiral compounds in a high stereoisomeric excess, e.g. a highenantiomeric excess, and may be tolerant to a wide range of solventsand/or functional groups. The present complexes may be particularlyadvantageous in the asymmetric synthesis of chiral compounds containingquaternary centres at a chiral carbon atom.

In another aspect, the present invention provides a compound of theformula (2):

wherein:

-   -   the moiety —O—C_(n)—O— is chiral and is an aliphatic or aromatic        diolate, wherein said diolate is optionally substituted;    -   each R^(E) is the same and is an achiral organic group; or R^(E)        and R^(E), together with the carbon atom to which they are        attached, form an achiral cyclic organic group;    -   each R^(F) is the same and is an achiral organic group; or R^(F)        and R^(F), together with the carbon atom to which they are        attached, form an achiral cyclic organic group; and    -   the moieties —CH(R^(E))₂ and —CH(R^(F))₂ as shown in formula (2)        are different; or a salt thereof.

In other aspects, the present invention relates to a process forproducing a chiral compound in a stereoisomeric excess, which processinvolves the use of a catalytic complex comprising a compound of formula(2) as a ligand. In embodiments, the chiral compound is produced via a1,4-conjugate addition reaction or a 1,6-conjugate addition reaction.Methods of producing compounds of formula (2) are also provided.Advantageously, the compounds of formula (2) can be readily prepared andmay not require the transformation of a chiral non-racemic amine or theseparation of diastereomers during preparation. The compounds may alsoexhibit desirable stereoselectivity when employed as ligands incatalytic complexes for use in asymmetric synthesis.

DESCRIPTION OF VARIOUS EMBODIMENTS

For the purposes of the present invention, the following terms as usedherein shall, unless otherwise indicated, be understood to have thefollowing meanings.

The term “alkyl” as used herein refers to a straight or branched chainalkyl moiety having from 1 to 30 carbon atoms. For instance, an alkylgroup may have from 1 to 20 carbon atoms, e.g. from 1 to 12 carbonatoms, e.g. from 1 to 10 carbon atoms. In particular, an alkyl group mayhave 1, 2, 3, 4, 5 or 6 carbon atoms (referred to herein as C₁₋₆ alkyl).Examples of alkyl groups include methyl, ethyl, propyl (n-propyl orisopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl andthe like. The term “alkylene” as used herein refers to a divalent alkylmoiety.

The term “alkenyl” as used herein refers to a straight or branched chainalkyl group having from 2 to 30 carbon atoms and having, in addition, atleast one carbon-carbon double bond, of either E or Z stereochemistrywhere applicable. For instance, an alkenyl group may have from 2 to 20carbon atoms, e.g. from 2 to 12 carbon atoms, e.g. from 2 to 10 carbonatoms. In particular, an alkenyl group may have 2, 3, 4, 5 or 6 carbonatoms. Examples of alkenyl groups include ethenyl, 2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl and the like.

The term “alkynyl” as used herein refers to a straight or branched chainalkyl group having from 2 to 30 carbon atoms and having, in addition, atleast one carbon-carbon triple bond. For instance, an alkynyl group mayhave from 2 to 20 carbon atoms, e.g. from 2 to 12 carbon atoms, e.g.from 2 to 10 carbon atoms. In particular, an alkynyl group may have 2,3, 4, 5 or 6 carbon atoms. Examples of alkynyl groups include ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.

The term “carbocyclyl” as used herein refers to a saturated (e.g.cycloalkyl) or unsaturated (e.g. cycloalkenyl or aryl) carbocyclic ringmoiety having from 3 to 30 carbon atoms. For instance, a carbocyclylgroup may have from 3 to 20 carbon atoms, e.g. from 3 to 16 carbonatoms, e.g. from 3 to 10 carbon atoms. In particular, a carbocyclylgroup may be a 5- or 6-membered ring system, which may be saturated orunsaturated. Examples of carbocyclic groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, fluorenyl,azulenyl, indenyl, anthryl and the like.

The term “cycloalkyl” as used herein refers to an aliphatic carbocyclicmoiety having from 3 to 20 ring carbon atoms. For instance, a cycloalkylgroup may have from 3 to 16 carbon atoms, e.g. from 3 to 10 carbonatoms. In particular, a cycloalkyl group may have 3, 4, 5 or 6 ringcarbon atoms. A cycloalkyl group may be a monocyclic, polycyclic (e.g.bicyclic) or bridged ring system. Examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and thelike.

The term “cycloalkenyl” as used herein refers to an aliphaticcarbocyclic moiety having from 5 to 20 ring carbon atoms and having, inaddition, at least one carbon-carbon double bond in the ring. Forinstance, a cycloalkenyl group may have from 5 to 16 carbon atoms, e.g.from 5 to 10 carbon atoms. In particular, a cycloalkenyl group may have5 or 6 ring carbon atoms. A cycloalkenyl group may be a monocyclic,polycyclic (e.g. bicyclic) or bridged ring system. Examples ofcycloalkenyl groups include cyclopentenyl, cyclohexenyl and the like.

The term “aryl” as used herein refers to an aromatic carbocyclic ringsystem having from 6 to 30 ring carbon atoms. For instance, an arylgroup may have from 6 to 16 ring carbon atoms, e.g. from 6 to 10 ringcarbon atoms. An aryl group may be a monocyclic aromatic ring system ora polycyclic ring system having two or more rings, at least one of whichis aromatic. Examples of aryl groups include phenyl, naphthyl,fluorenyl, azulenyl, indenyl, anthryl and the like.

The term “aralkyl” as used herein refers to an alkyl group substitutedwith an aryl group, wherein the alkyl and aryl groups are as definedherein. An example of an aralkyl group is benzyl.

The term “heterocyclyl” as used herein refers to a saturated (e.g.heterocycloalkyl) or unsaturated (e.g. heterocycloalkenyl or heteroaryl)heterocyclic ring moiety having from 3 to 30 ring atoms, wherein saidring atoms include at least one ring carbon atom and at least one ringheteroatom selected from nitrogen, oxygen, phosphorus, silicon andsulphur. For instance, a heterocyclyl group may have from 3 to 20 ringatoms, e.g. from 3 to 16 ring atoms, e.g. from 3 to 10 ring atoms. Inparticular, a heterocyclyl group may have 5 or 6 ring atoms, and may besaturated or unsaturated. Examples of heterocyclic groups includeimidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl,thianthrenyl, isobenzofuranyl, chromenyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl,pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl,pyridazinyl, morpholinyl, thiomorpholinyl, indolizinyl, indolyl,cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, isoquinolyl,quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl,dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl,quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl,phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl,oxiranyl, azirinyl, 1,2-oxathiolanyl, chromanyl and the like.

The term “heterocycloalkyl” as used herein refers to a saturatedheterocyclic moiety having from 3 to 10 ring carbon atoms and 1, 2, 3, 4or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus andsulphur. The group may be a monocyclic or polycyclic ring system.Examples of heterocycloalkyl groups include azetidinyl, pyrrolidinyl,tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl,indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl,quinolizidinyl, tetrahydropyranyl, and the like.

The term “heterocycloalkenyl” as used herein refers to a saturatedheterocyclic moiety having from 3 to 10 ring carbon atoms and 1, 2, 3, 4or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus andsulphur, and having, in addition, at least one carbon-carbon double bondin the ring. The group may be a monocyclic or polycyclic ring system. Anexample of a heterocycloalkenyl group is pyranyl.

The term “heteroaryl” as used herein refers to an aromatic heterocyclicring system having from 5 to 30 ring atoms, wherein said ring atomsinclude at least one ring carbon atom and at least one ring heteroatomselected from nitrogen, oxygen and sulphur. The group may be amonocyclic ring system or a polycyclic (e.g. bicyclic) ring systemhaving two or more rings, at least one of which is aromatic. Examples ofheteroaryl groups include pyridazinyl, pyrimidinyl, furanyl,benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl,pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl,quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl,oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, isoquinolinyl,quinazolinyl and the like.

The terms “halogen” and “halo” as used herein refer to F, Cl, Br or I.

The term “optionally substituted” as used herein means unsubstituted orsubstituted.

The term “substituted” as used herein in connection with a chemicalgroup means that one or more (e.g. 1, 2, 3, 4 or 5) of the hydrogenatoms in that group are replaced independently of each other by acorresponding number of substituents. It will, of course, be understoodthat the one or more substituents may only be at positions where theyare chemically possible, i.e. that any substitution is in accordancewith permitted valence of the substituted atom and the substituent, andthat the substitution results in a stable compound. The term iscontemplated to include all permissible substituents of a chemical groupor compound. It will be understood by those skilled in the art that oneor more hydrogen atoms on a given substituent can themselves besubstituted, if appropriate.

Examples of substituents include acyl, alkoxy, alkoxycarbonyl,alkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, amino, aminoalkyl,aralkyl, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, hydroxy,formyl, nitro, alkyl (optionally substituted with e.g. alkoxy, hydroxy,haloalkoxy, halogen or haloalkyl), aryl (optionally substituted withe.g. alkoxy, hydroxy, haloalkoxy, halogen, alkyl or haloalkyl),heteroaryl (optionally substituted with e.g. alkoxy, hydroxy,haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl (optionallysubstituted with e.g. alkoxy, hydroxy, haloalkoxy, halogen, alkyl orhaloalkyl), aminoacyl, aminosulfonyl, acylamino, sulfonylamino,heteroarylalkyl, aryloxy, heteroaryloxy, arylalkyloxy andheteroarylalkyloxy. In an embodiment, said one or more substituents areeach independently selected from C₁₋₆ alkyl (e.g. methyl), aryl, haloand hydroxy.

Where two or more moieties are described as being “each independently”selected from a list of moieties, this means that the moieties may bethe same or different. The identity of each moiety is thereforeindependent of the identities of the one or more other moieties. Wheremultiple substituents are indicated as being attached to a structure, itwill be understood that the substituents can be the same or different.

The term “electron withdrawing group” as used herein refers to any atomor group having an electronegativity greater than that of a hydrogenatom, wherein electronegativity is as defined on the Pauling scale. Aquantification of the level of electron withdrawing capability is givenby the Hammett sigma (σ) constant. This constant is well known in theart (see e.g. “Advanced Organic Chemistry”, J. March, McGraw Hill, NewYork, 2007). The Hammett sigma constant values are generally positivefor electron withdrawing groups.

The term “π-bond” as used herein refers to a chemical bond formed by theoverlap of p orbitals on adjacent atoms, perpendicular to any sigma (σ)bonds between the same atoms. A π-bond is generally a double or triplebond. Examples of π-bonds include C═O, C≡C, C═O, C═N, C≡N, N═O and S═Obonds.

The term “alkene bond” as used herein refers to an aliphaticcarbon-carbon double (C═O) bond.

The term “organic group” as used herein refers to a chemical groupcomprising at least one carbon atom and one or more atoms in addition,e.g. one or more atoms selected from hydrogen, oxygen, nitrogen,sulphur, phosphorus, halogen, silicon, boron and combinations thereof.Examples of organic groups include alkyl, aryl, aralkyl, cycloalkyl,cycloalkenyl, heterocyclyl and combinations thereof, wherein any of saidgroups may be unsubstituted or substituted by one or more substituents.

In a first aspect, the present invention provides a catalytic complexcomprising a metal, one or more ligands and one or more counterions,wherein said one or more ligands include a non-racemic chiral ligand andwherein said one or more counterions include a triflimide counterion. Inthis regard, the use of a triflimide anion (i.e. [N(SO₂CF₃)₂]⁻; alsoreferred to herein as “NTf₂ ⁻”) as a counterion may result in improvedstereoselectivity and provide for an increased stereoisomeric excess inasymmetric reactions, particularly in asymmetric conjugate additionreactions.

The catalytic complex according to said first aspect of the inventioncontains one or more counterions, at least one of which is a triflimideanion. The one or more counterions serve to provide electroneutrality tothe catalytic complex and will typically be non-coordinatingcounterions. In embodiments, the catalytic complex comprises one or morecounterions in addition to the triflimide anion. Where present, anyadditional counterions will normally be anionic. In embodiments, thetriflimide anion is the only counterion that is present in the catalyticcomplex.

In an embodiment, the metal is a transition metal, e.g. selected fromcopper, cobalt, iridium, rhodium, ruthenium, nickel, iron, palladium,gold, silver and platinum. In a preferred embodiment, the complexcomprises copper. More preferably, the metal is copper (I). The use ofcopper is particularly desirable as it can catalyse the conjugateaddition of alkylzirconocenes formed in situ from alkenes with highoverall yield.

The catalytic complex comprises one or more ligands, at least one ofwhich is a non-racemic chiral racemic ligand. The one or more ligandswill normally be bound to the metal atom via a coordinate bond.Typically, the one or more ligands will be uncharged such that they donot counter the ionic charge of any other species in the complex.

The non-racemic chiral ligand may be a chelating ligand or anon-chelating ligand. Examples of suitable ligands include phosphines,bisphosphines, amines, diamines, imines, arsines, sulfides, sulfoxides,carbenes (e.g. N-heterocyclic carbenes), peptides and hybrids thereof,including hybrids of phosphines with amines, hybrids of phosphines withpeptides, and hybrids of phosphines with sulfides.

In embodiments, the catalytic complex comprises one or more otherligands in addition to the non-racemic chiral ligand. Thus, for example,it may be necessary in some instances for the catalytic complex toinclude one or more additional ligands in order to obtain a stablecomplex. In other embodiments, the non-racemic chiral ligand is the onlyligand that is present in the complex.

In an embodiment, the non-racemic chiral ligand is a phosphoramiditeligand. In a particular embodiment, the non-racemic chiral ligand is aphosphoramidite ligand of the formula (1):

wherein:

-   -   the moiety —O—C_(n)—O— is an aliphatic or aromatic diolate,        wherein said diolate is optionally substituted; and    -   R^(A), R^(B), R^(C) and R^(D) are each independently selected        from alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl,        heterocyclyl and combinations thereof, any of which is        optionally substituted.

In an embodiment, the moiety —O—C_(n)—O— in formula (1) is chiral. In anembodiment, the moiety —O—C_(n)—O— exhibits axial chirality. In anembodiment, the moiety —O—C_(n)—O— is a moiety derived from a binaphtholcompound. The term “moiety derived from a binaphthol compound” as usedherein refers to a moiety formed by removing hydrogen atoms from the twohydroxyl groups of a binaphthol compound. The binaphthol compound may beunsubstituted or substituted by one or more substituents, in addition tothe two hydroxyl groups. In an embodiment, the moiety —O—C_(n)—O— is amoiety derived from an unsubstituted binaphthol compound. In anembodiment, the binaphthol compound is partially hydrogenated. In aparticular embodiment, the binaphthol compound is (R)-1,1′-bi-2-naphtholor (S)-1,1′-bi-2-naphthol.

In an embodiment, R^(A), R^(B), R^(C) and R^(D) are each independentlyselected from alkyl and aryl, either of which is optionally substituted.

In an embodiment, R^(A), R^(B), R^(C) and R^(D) are each independentlyselected from C₁₋₆ alkyl (e.g. methyl or ethyl) and aryl (e.g. phenyl),either of which is optionally substituted.

In an embodiment, at least one (e.g. two) of R^(A), R^(B), R^(C) andR^(D) is C₁₋₆ alkyl (e.g. methyl or ethyl) and the one or more othersare selected from aryl (e.g. phenyl), wherein said C₁₋₆ alkyl and arylgroups are optionally substituted.

In an embodiment, R^(A) and R^(D) are each independently aryl (e.g.phenyl) and R^(B) and R^(C) are each independently C₁₋₆ alkyl (e.g.methyl or ethyl), wherein said C₁₋₆ alkyl and aryl groups are optionallysubstituted.

In an embodiment, R^(A) and R^(B) are each independently aryl (e.g.phenyl) and R^(C) and R^(D) are each independently C₁₋₆ alkyl (e.g.methyl or ethyl), wherein said C₁₋₆ alkyl and aryl groups are optionallysubstituted.

In an embodiment, at least one of R^(A), R^(B), R^(C) and R^(D) issubstituted with one or more (e.g. 1, 2 or 3) substituents. In anembodiment, the one or more substituents are each independently selectedfrom acyl, alkoxy, alkoxycarbonyl, alkylamino, alkylsulfinyl,alkylsulfonyl, alkylthio, amino, aminoalkyl, aralkyl, cyano,dialkylamino, halo, haloalkoxy, haloalkyl, hydroxy, formyl, nitro, alkyl(optionally substituted with e.g. alkoxy, hydroxy, haloalkoxy, halogenor haloalkyl), aryl (optionally substituted with e.g. alkoxy, hydroxy,haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionallysubstituted with e.g. alkoxy, hydroxy, haloalkoxy, halogen, alkyl orhaloalkyl), heterocycloalkyl (optionally substituted with e.g. alkoxy,hydroxy, haloalkoxy, halogen, alkyl or haloalkyl), aminoacyl,aminosulfonyl, acylamino, sulfonylamino, heteroarylalkyl, aryloxy,heteroaryloxy, arylalkyloxy and heteroarylalkyloxy. In an embodiment,said one or more substituents are each independently selected from C₁₋₆alkyl (e.g. methyl), halo and hydroxy.

In an embodiment, each of R^(A), R^(B), R^(C) and R^(D) isunsubstituted.

In another embodiment, the non-racemic chiral ligand is a compound ofthe formula (2) as defined herein.

In a preferred embodiment, the non-racemic chiral ligand is a compoundof the formula (A), (B), (C) or (D):

In an embodiment, the catalytic complex is of the formula MLZ, wherein Mis a metal, L is a non-racemic chiral ligand and Z is a triflimidecounterion. M, L and Z may be as described in any of the embodiments setforth above. In embodiments, M is copper (I). In embodiments, L is aphosphoramidite ligand, e.g. a phosphoramidite ligand of any of theformulae (1), (2), (A), (B), (C) and (D) as described herein.

In an embodiment, the catalytic complex is of one of the followingformulae:

The catalytic complex may be prepared following procedures known in theart. The catalytic complex will generally be prepared by contacting ametal, the non-racemic chiral ligand and any other ligands with atriflimide anion and any other counterions. The triflimide anion ispreferably in the form of a metal salt. In an embodiment, the catalyticcomplex is prepared by contacting a triflimide anion with a catalystprecursor in which the metal is bound to said one or more ligands. In anembodiment, the triflimide anion is in the form of a triflimide salt.Preferably, the triflimide salt is silver triflimide. In this regard, ithas been found that silver triflimide complexes may be particularlyeffective for anion exchange with metal salts and, in particular, coppersalts.

The complex may be formed as a pre-made catalyst or may be generated insitu during the course of a chemical reaction, e.g. during the course ofan asymmetric conjugate addition reaction. The complex may be formed byconverting a catalyst precursor into the active form. The complex may beprepared by stirring the metal, one or more ligands, one or morecounterions and any other components under appropriate conditions.

Suitable processes and conditions for forming the catalytic complexes ofthe present invention are described in the Examples herein. By way ofillustration, and without limitation, a catalytic complex comprisingcopper, a non-racemic chiral phosphoramidite ligand and a triflimidecounterion may be prepared according to the following procedure. Acopper salt and one equivalent of phosphoramidite ligand are added to aflame dried Schlenk flask, at room temperature under an argonatmosphere. Dry dichloromethane (DCM) is then added and the mixture isstirred for one hour to create a clear solution. One equivalent ofsilver triflimide is added to the clear solution and stirred for afurther 20 minutes. On addition of silver triflimide, the solution turnsgrey and a silver chloride precipitate forms. The resulting solution iscannula filtrated into another Schlenk flask. The solvent is then gentlyremoved by use of an oil-pump vacuum (with liquid nitrogen trapping).The resulting off-white solid is dried for at least one hour underoil-pump vacuum and is then stored under argon.

In another aspect, the present invention provides a compound of theformula (2):

wherein:

-   -   the moiety —O—C_(n)—O— is chiral and is an aliphatic or aromatic        diolate, wherein said diolate is optionally substituted;    -   each R^(E) is the same and is an achiral organic group; or R^(E)        and R^(E), together with the carbon atom to which they are        attached, form an achiral cyclic organic group;    -   each R^(F) is the same and is an achiral organic group; or R^(F)        and R^(F), together with the carbon atom to which they are        attached, form an achiral cyclic organic group; and    -   the moieties —CH(R^(E))₂ and —CH(R^(F))₂ as shown in formula (2)        are different;        or a salt thereof.

In an embodiment, the moiety —O—C_(n)—O— in formula (2) exhibits axialchirality. In an embodiment, the moiety —O—C_(n)—O— is a moiety derivedfrom a binaphthol compound. The term “moiety derived from a binaphtholcompound” is as defined above. The binaphthol compound may beunsubstituted or substituted by one or more substituents, in addition tothe two hydroxyl groups. In an embodiment, the moiety —O—C_(n)—O— is amoiety derived from an unsubstituted binaphthol compound. In anembodiment, the binaphthol compound is partially hydrogenated. In aparticular embodiment, the binaphthol compound is (R)-1,1′-bi-2-naphtholor (S)-1,1′-bi-2-naphthol.

In an embodiment, each R^(E) is optionally substituted aryl. In anembodiment, each R^(E) is phenyl or naphthyl, either of which isoptionally substituted. In an embodiment, each R^(E) is phenyl, whereinsaid phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl (e.g. methyl),halogen (e.g. fluoro), trifluoromethyl and C₁₋₆ alkoxy (e.g. methoxy).In an embodiment, each R^(E) is naphthyl. In an embodiment, each R^(E)is phenyl and the R^(E) moieties are joined via an alkylene bridge, e.g.a C₁₋₆ alkylene bridge.

In an embodiment, each R^(F) is optionally substituted alkyl, e.g.optionally substituted C₁₋₆ alkyl. In an embodiment, each R^(F) is C₁₋₆alkyl. In an embodiment, each R^(F) is methyl, ethyl or propyl(isopropyl or n-propyl). In an embodiment, each R^(F) is methyl.

In an embodiment, R^(F) and R^(F), together with the carbon atom towhich they are attached, form an achiral cyclic organic group. In anembodiment, the achiral cyclic organic group is an optionallysubstituted cycloalkyl group. In an embodiment, the achiral cyclicorganic group is cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, anyof which is optionally substituted. In an embodiment, the achiral cyclicorganic group is cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

In an embodiment, each R^(E) is optionally substituted aryl (e.g.optionally substituted phenyl or naphthyl); and each R^(F) is optionallysubstituted alkyl (e.g. optionally substituted C₁₋₆ alkyl), or R^(F) andR^(F), together with the carbon atom to which they are attached, form anachiral cyclic organic group which is an optionally substitutedcycloalkyl group.

In an embodiment, each R^(E) is optionally substituted phenyl; and eachR^(F) is optionally substituted C₁₋₆ alkyl (e.g. methyl, ethyl orpropyl), or R^(F) and R^(F), together with the carbon atom to which theyare attached, form cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,any of which is optionally substituted.

In an embodiment, each R^(E) is phenyl, wherein said phenyl isunsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from C₁₋₆ alkyl (e.g. methyl), halogen (e.g.fluoro), trifluoromethyl and C₁₋₆ alkoxy (e.g. methoxy); and each R^(F)is methyl.

In an embodiment, the compound of formula (2) is selected from thefollowing compounds:

In an embodiment, the moiety —O—C_(n)—O— in each of the above compoundsexhibits axial chirality. In an embodiment, the moiety —O—C_(n)—O— is amoiety derived from a binaphthol compound. In a particular embodiment,the binaphthol compound is (R)-1,1′-bi-2-naphthol or(S)-1,1′-bi-2-naphthol.

In another embodiment, the compound of formula (2) is selected from thefollowing compounds:

In an embodiment, the moiety —O—C_(n)—O— in each of the above compoundsexhibits axial chirality. In an embodiment, the moiety —O—C_(n)—O— is amoiety derived from a binaphthol compound. In a particular embodiment,the binaphthol compound is (R)-1,1′-bi-2-naphthol or(S)-1,1′-bi-2-naphthol.

In a preferred embodiment, the compound is a compound of the formula (C)or (D):

All stereoisomers of the compounds of formula (2) are included withinthe scope of the present invention. Where a single enantiomer ordiastereoisomer is disclosed, the present invention also extends to theother enantiomers or diastereoisomers.

Also provided is a catalytic complex comprising a metal and one or moreligands, wherein said one or more ligands include a compound of theformula (2).

The catalytic complex may contain one or more ligands in addition to thecompound of formula (2). For instance, the catalytic complex may containone or more additional ligands selected from phosphines, bisphosphines,amines, diamines, imines, arsines, sulfides, sulfoxides, carbenes (e.g.N-heterocyclic carbenes), peptides and hybrids thereof, includinghybrids of phosphines with amines, hybrids of phosphines with peptides,and hybrids of phosphines with sulfides. In an embodiment, the compoundof formula (2) is the only ligand that is present in the complex.

In an embodiment, the metal is a transition metal, e.g. selected fromcopper, cobalt, iridium, rhodium, ruthenium, nickel, iron, palladium,gold, silver and platinum. In a preferred embodiment, the complexcomprises copper. More preferably, the metal is copper (I).

The catalytic complex will typically comprise one or more counterions.In an embodiment, the one or more counterions are selected fromtriflate, triflimide, tetrafluoroborate ([BF₄]⁻), hexafluorophosphate([PF₆]⁻), hexafluoroantimonate ([SbF₆]⁻), perchlorate ([ClO₄]⁻) and BARF([B[3,5-(CF₃)₂C₆H₃]₄]⁻). In a preferred embodiment, the catalyticcomplex contains triflate or triflimide as a counterion.

In an embodiment, the catalytic complex is of the formula M′L′Z′,wherein M′ is a metal, L′ is a ligand which is a compound of the formula(2) and Z′ is a counterion. M′ and Z′ may be as described in any of theembodiments set forth above. In embodiments, M′ is copper (I). In anembodiment, Z′ is a triflate or triflimide anion.

In an embodiment, the catalytic complex is of one of the followingformulae:

Also provided is a process for producing a compound of formula (2), theprocess comprising contacting an optionally substituted, aliphatic oraromatic diol of the formula HO—C_(n)—OH with a compound of the formula(3):

wherein:

-   -   each R is independently a leaving group; and    -   R^(E) and R^(F) are as defined above in relation to formula (2).

In an embodiment, each R is independently a halogen. In an embodiment,each R is chlorine.

In an embodiment, the diol is a binaphthol compound, e.g.(R)-1,1′-bi-2-naphthol or (S)-1,1′-bi-2-naphthol. In an embodiment, themoiety —N(CHR^(E)R^(E))CHR^(F)R^(F) in formula (3) isN-benzhydrylpropan-2-amino.

Suitable procedures for forming the compound of formula (2) from thecompound of formula (3) and said diol are described herein and are knownin the art (see e.g. Trost et al, J. Am. Chem. Soc., 2011, 133, 48,19483-19497).

Suitable procedures for forming the compound of formula (3) aredescribed herein and are known in the art.

In a preferred embodiment, the compound of formula (3) is obtained bycontacting a compound of the formula PR₃ with a compound of the formulaHN(CHR^(E)R^(E))CHR^(F)R^(F).

Preferably, the compound of the formula HN(CHR^(E)R^(E))CHR^(F)R^(F) isin turn obtained by reductive amination of a compound of the formulaR^(F)C(O)R^(F) and a compound of the formula H₂NCHR^(E)R^(E). Suitableprocedures for performing the reductive amination reaction are describedherein and are known in the art (see e.g. Davies, S. et al, Org. Biomol.Chem., 2004, 3337-3354; Rahman et al, Org. Biomol. Chem., 2004, 2, 11,1612-1616; Smith et al, Org. Lett., 2008, 1657-1659; and Mukherjee etal, J. Am. Chem. Soc., 2007, 129, 37, 11336-11337). The compoundsR^(F)C(O)R^(F) and H₂NCHR^(E)R^(E) may be readily available fromcommercial sources or may be readily synthesised according to literatureprocedures. In particular, the compound R^(F)C(O)R^(F) may be an acyclicor cyclic ketone that is readily available from commercial sources.

By way of illustration, and without limitation, a compound of formula(C) may be obtained by contacting (R)-1,1′-bi-2-naphthol with a compoundof the formula R₂PR′, wherein each R is independently a leaving group(e.g. chlorine or other halogen) and R′ is N-benzhydrylpropan-2-amino.The compound of the formula R₂PR′ may be obtained by contacting acompound of the formula PR₃ with N-benzhydrylpropan-2-amine. The lattercompound may, in turn, be obtained by reductive amination of acetone anddiphenylmethanamine. A process for the preparation of the compound offormula (C) is described in the Examples herein.

Advantageously, the compounds of formula (2) can be readily preparedfrom commercially available starting materials, and their preparationmay not require the transformation of a chiral non-racemic amine or theseparation of diastereomers during preparation. The compounds may alsoexhibit desirable stereoselectivity when they are employed in catalyticcomplexes for use in asymmetric synthesis.

The catalytic complexes of the present invention may be used inprocesses for the production of chiral compounds in a stereoisomericexcess (e.g. an enantiomeric excess or a diastereomeric excess). Inparticular, the catalytic complexes may be used in processes for theasymmetric synthesis of chiral compounds, e.g. in processes whichinvolve an asymmetric 1,4-conjugate addition reaction or an asymmetric1,6-conjugate addition reaction. Examples of such processes aredescribed in PCT Patent Application No. PCT/GB2012/052537, filed 12 Oct.2012 and entitled “Asymmetric Synthesis of Organic Compounds”, thecontents of which are incorporated herein by reference in theirentirety.

In particular, the present invention provides a process for producing achiral compound in a stereoisomeric excess, the process comprising:

-   -   contacting a first compound comprising an alkene bond with a        hydrometallating agent, wherein the first compound and the        hydrometallating agent are contacted under conditions such that        the first compound is hydrometallated by said hydrometallating        agent; and    -   (ii) contacting the hydrometallated first compound with a second        compound, wherein the second compound comprises a conjugated        π-bond system which is capable of undergoing a 1,4-conjugate        addition reaction or a 1,6-conjugate addition reaction and which        has a carbon atom at said 4-position or said 6-position        respectively, wherein the hydrometallated first compound and the        second compound are contacted under conditions such that they        undergo an asymmetric 1,4-conjugate addition reaction or an        asymmetric 1,6-conjugate addition reaction in which a carbon        atom of said hydrometallated first compound binds to the carbon        atom at said 4-position or said 6-position of the second        compound, forming a stereoisomeric excess of a compound having a        chiral carbon atom at said 4-position or said 6-position;    -   wherein said asymmetric 1,4-conjugate addition reaction or said        asymmetric 1,6-conjugate addition reaction is performed in the        presence of a catalytic complex of the present invention.

The first compound comprises at least one alkene bond, i.e. at least onealiphatic carbon-carbon double (C═O) bond. The first compound may be anacyclic compound, a cyclic compound, or may comprise an acyclic portionand a cyclic portion. The compound may consist exclusively of carbon andhydrogen atoms, or may comprise one or more other atoms in addition. Inan embodiment, the first compound is a straight or branched alkenecompound having from 2 to 30 carbon atoms, e.g. from 2 to 20 carbonatoms, e.g. from 2 to 12 carbon atoms, e.g. from 2 to 10 carbon atoms,e.g. 2, 3, 4, 5 or 6 carbon atoms. The alkene compound may beunsubstituted or substituted with one or more substituents, e.g. with 1,2, 3, 4 or 5 substituents selected from R^(a); hydrocarbyl optionallysubstituted with 1, 2, 3, 4 or 5 R^(a); and —(CH₂)_(j)-heterocyclyloptionally substituted with 1, 2, 3, 4 or 5 R^(a); wherein R^(a) and jare as defined elsewhere herein.

Preferably, the first compound is a terminal alkene. Terminal alkenesare typically produced annually on the megaton scale, and are among themost readily available organic molecules. These inexpensive rawmaterials are feedstocks for the preparation of many classes of organiccompounds. Catalytic intermolecular reactions using these alkenes mayhave a tremendous value-added component because they convert inexpensiveraw materials into highly functionalised compounds. Alternatively, thefirst compound may be an internal alkene; such compounds are alsoreadily available and commonly used in chemistry.

The first compound is reacted with a hydrometallating agent underconditions such that the first compound is hydrometallated.Hydrometallation of the first compound will typically result in theaddition of a metal atom to one carbon atom of the alkene bond and ahydride ligand to the other. In certain instances, the first compoundmay undergo one or more intramolecular rearrangements (e.g. beta hydrideelimination followed by further hydrometallation) in which the alkenebond relocates to a different position within the first compound, priorto or during reaction with the hydrometallating agent. Thus, forinstance, the hydrometallation reaction may result in the attachment ofthe metal at the sterically less hindered position of the alkene chain.In this case, hydrometallation may occur either by regiospecificaddition of the agent to a terminal alkene bond or by addition of theagent to an internal alkene bond followed by rearrangement via metalhydride elimination and readdition to place the metal at a less hinderedposition of the alkene chain (see e.g. Schwartz et al, Angew. Chem. Int.Ed., 1976, 6, 333). All such hydrometallation reactions fall within thescope of the present invention.

Various hydrometallating agents are known in the art. Thehydrometallating agent may comprise a metal (which term encompassesmetalloids) and at least one hydride group. By way of illustration, thehydrometallating agent may comprise at least one metal selected fromzirconium, titanium, hafnium, niobium, tantalum, boron, aluminium, tin,silicon, magnesium, zinc, palladium, iridium, copper, rhodium,ruthenium, platinum, rhenium, nickel and the like. Preferably, thehydrometallating agent comprises a transition metal. More preferably,the hydrometallating agent comprises zirconium. The hydrometallatingagent may be in the form of a metal complex comprising a metal (e.g. atransition metal) bound to one or more ligands, at least one of which isa hydride ligand.

In a preferred embodiment, the hydrometallating agent is a zirconiumcomplex, e.g. a zirconium halohydride complex. In an embodiment, thehydrometallating agent is a zirconium complex of the formula HZrR₂X,wherein each R is independently an optionally substituted 6π electrondonating ligand (e.g. having 5 carbon atoms, e.g. a π-cyclopentadienylligand) and X is another ligand, e.g. selected from halogen, triflates,alcohols and nitrogen-containing compounds. In a preferred embodiment,the hydrometallating agent is a zirconium complex of the formulaHZrCp₂X, wherein each Cp is an optionally substituted π-cyclopentadienylligand and X is a ligand selected from halogen, triflates, alcohols andnitrogen-containing compounds. Preferably, X is halogen. Particularlypreferred is a zirconium complex of the formula HZrCp₂Cl, which iscommonly known in the art as the “Schwartz reagent” (see Schwartz et al,J. Am. Chem. Soc., 96, 8115-8116, 1974).

The hydrometallating agent may be prepared according to procedures knownin the art (see e.g. Org. Syn., coll. Col. 9, p. 162 (1998), vol. 71, p77 (1993); Negishi, Tet. Lett. 1984, 25, 3407; Buchwald, Tet. Lett.1987, 28, 3895; Lipshutz, Tet. Lett., 1990, 31, 7257; Negishi, J. Org.Chem. 1991, 56, 2590; and Negishi, Eur. J. Org. Chem. 1999, 969).

The hydrometallated first compound is reacted with a second compound,the second compound comprising a conjugated π-bond system which iscapable of undergoing a 1,4-conjugate addition reaction or a1,6-conjugate addition reaction and which has a carbon atom at the 4- orthe 6-position respectively. The second compound may be any compoundcapable of acting as a so-called “Michael acceptor”, and will typicallybe an electrophilic alkene compound. Exemplary compounds includeα,β-unsaturated carbonyl compounds (e.g. enones, acrylate esters,acrylamides, maleimides, alkyl methacrylates, acrylamides and vinylketones), cyanoacrylates, vinyl sulfones, nitro ethylenes, vinylphosphonates, acrylonitriles, vinyl pyridines and azo compounds. In apreferred embodiment, the second compound is an α,β-unsaturated carbonylcompound, e.g. an enone.

In an embodiment, the second compound is a dienone. In an embodiment,the second compound is a steroid compound. In a particular embodiment,the second compound is a steroid compound comprising a dienone group.

In an embodiment, the hydrometallated first compound and the secondcompound are contacted under conditions such that they undergo anasymmetric 1,4-conjugate addition reaction to form a chiral compound.Thus, a carbon atom of said hydrometallated first compound to which themetal is attached may bind to the carbon atom at said 4-position of thesecond compound, forming a stereoisomeric excess of a compound having achiral carbon atom at said 4-position.

Accordingly, in one embodiment, the process comprises:

-   -   contacting a first compound comprising an alkene bond with a        hydrometallating agent, wherein the first compound and the        hydrometallating agent are contacted under conditions such that        the first compound is hydrometallated by said hydrometallating        agent; and    -   (ii) contacting the hydrometallated first compound with a second        compound, wherein the second compound comprises a conjugated        π-bond system which is capable of undergoing a 1,4-conjugate        addition reaction and which has a carbon atom at said        4-position, wherein the hydrometallated first compound and the        second compound are contacted under conditions such that they        undergo an asymmetric 1,4-conjugate addition reaction in which a        carbon atom of said hydrometallated first compound binds to the        carbon atom at said 4-position of the second compound, forming a        stereoisomeric excess of a compound having a chiral carbon atom        at said 4-position, wherein said asymmetric conjugate addition        reaction is performed in the presence of a catalytic complex of        the present invention.

In an embodiment, the asymmetric conjugate addition reaction results inthe formation of a quaternary centre at the 4-position.

In an embodiment, the second compound is a dienone and the asymmetricconjugate addition reaction results in the formation of a quaternarycentre at the 4-position.

In a particular embodiment, the present invention provides a process forproducing a chiral compound of the formula (IV) in a stereoisomericexcess (e.g. an enantiomeric or diastereomeric excess):

wherein

-   -   R¹, R², R³ and R⁴ are each independently selected from hydrogen,        R^(a), hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5        R^(a); and —(CH₂)_(j)-heterocyclyl optionally substituted with        1, 2, 3, 4 or 5 R^(a);    -   or R¹ and R³ taken together with the carbon atoms to which they        are attached may form a carbocyclic or heterocyclic group, which        group is optionally substituted with 1, 2, 3, 4 or 5 R^(a);    -   R⁵, R⁶ and R⁷ are each independently selected from hydrogen,        R^(a), hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5        R^(a); and —(CH₂)_(j)-heterocyclyl optionally substituted with        1, 2, 3, 4 or 5 R^(a);    -   or R⁵ and one of R⁷ and X, taken together with the carbon atoms        to which they are attached, may form a carbocyclic or        heterocyclic group, which group is optionally substituted with        1, 2, 3, 4 or 5 R^(a);    -   X and Y taken together form an electron withdrawing group in        which the bond between X and Y is a π-bond,    -   each R^(a) is independently selected from halogen,        trifluoromethyl, cyano, nitro, oxo, ═NR^(b), —OR^(b),        —C(O)R^(b), —C(O)N(R^(b))R^(c), —C(O)OR^(b), —C(O)SR^(b),        —C(O)SeR^(b), —OC(O)R^(b), —S(O)_(k)R^(b),        —S(O)_(k)N(R^(b))R^(c), —N(R^(b))R^(c), —N(R^(b))N(R^(b))R^(c),        —N(R^(b))C(O)R^(c) and —N(R^(b))S(O)_(k)R^(b),    -   R^(b) and R^(c) are each independently hydrogen or selected from        hydrocarbyl and —(CH₂)_(j)-heterocyclyl, either of which is        optionally substituted with 1, 2, 3, 4 or 5 substituents        independently selected from halogen, oxo, cyano, amino, hydroxy,        alkyl and alkoxy;    -   j is 0, 1, 2, 3, 4, 5 or 6;    -   k is 0, 1 or 2; and    -   the asterisk * designates a chiral centre of (R) or (S)        configuration.

The compound of formula (IV) may be obtained by first contacting acompound comprising an alkene bond with a hydrometallating agent of theformula HM, wherein M comprises a metal (e.g. a transition metal),wherein said compound and the hydrometallating agent are contacted underconditions such that the compounds react to form a compound of theformula (II):

Thus, for instance, the process may comprise contacting an alkenecompound of the formula (I):

with a hydrometallating agent of the formula HM under conditions suchthat the compounds react to form the compound of formula (II).

The compound of the formula (II) is then contacted with a compound ofthe formula (III):

wherein the compound of formula (II) and the compound of formula (III)are contacted under conditions such that they undergo an asymmetric1,4-conjugate addition reaction in which a stereoisomeric excess of acompound of formula (IV) is formed. The conjugate addition reaction isperformed in the presence of a catalytic complex of the presentinvention.

In embodiments, one or more of the following may apply: (i) R¹ ishydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R^(a); (ii) R¹is alkyl, cycloalkyl or aralkyl, any of which is optionally substitutedwith 1, 2, 3, 4 or 5 R^(a); (iii) R³ is hydrogen or hydrocarbyloptionally substituted with 1, 2, 3, 4 or 5 R^(a); (iv) R³ is hydrogenor alkyl optionally substituted with 1, 2, 3, 4 or 5 R^(a); (v) R¹ andR³ taken together with the carbon atoms to which they are attached form,in the compounds of formulae (II) and (IV), cycloalkyl optionallysubstituted with 1, 2, 3, 4 or 5 R^(a); and (vi) R² and R⁴ are eachhydrogen.

In an embodiment, M comprises a metal selected from zirconium, titanium,hafnium, niobium, tantalum, boron, aluminium, tin, silicon, magnesium,zinc, palladium, iridium, copper, rhodium, ruthenium, platinum, rheniumand nickel. Preferably, M comprises a transition metal.

More preferably, the compound of formula (II) is obtained byhydrozirconation of the compound comprising said alkene bond, e.g. byhydrozirconation of a compound of the formula (I). Thus, in a preferredembodiment, the hydrometallating agent HM comprises zirconium.Preferably, the hydrometallating agent is a zirconium complex of theformula HZrR₂X as defined above. In a preferred embodiment, thehydrometallating agent is a zirconium complex of the formula HZrCp₂X asdefined above. Particularly preferred is a zirconium complex of theformula HZrCp₂Cl (the Schwartz reagent).

In embodiments, one or more of the following may apply: (i) R⁵ ishydrogen or hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5R^(a); (ii) R⁵ is hydrogen or alkyl optionally substituted with 1, 2, 3,4 or 5 R^(a); (iii) R⁶ is hydrogen or hydrocarbyl optionally substitutedwith 1, 2, 3, 4 or 5 R^(a); (iv) R⁶ is hydrogen or alkyl optionallysubstituted with 1, 2, 3, 4 or 5 R^(a); and (v) R⁵ and R⁷ taken togetherwith the carbon atoms to which they are attached form cycloalkenyloptionally substituted with 1, 2, 3, 4 or 5 R^(a).

In an embodiment, R⁵ and R⁶ are each other than hydrogen such that thechiral centre is a quaternary centre.

In an embodiment:

-   -   X and Y taken together form —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R⁹, —CN,        —C(O)SR⁸, —C(O)SeR⁸, —SO₂R⁸, —SO₂NR⁸R⁹ or —NO₂, wherein R⁸ and        R⁹ are each independently hydrogen or selected from hydrocarbyl        and —(CH₂)_(j)-heterocyclyl, either of which is optionally        substituted with 1, 2, 3, 4 or 5 substituents independently        selected from halogen, oxo, cyano, amino, hydroxy, C₁₋₆ alkyl        and C₁₋₆ alkoxy; or    -   X is carbon and Y is oxo; and X and R⁵ taken together with the        carbon atoms to which they are attached form a carbocyclic group        or a heterocyclic group (e.g. a lactone, thiolactone or lactam),        either of which is optionally substituted with 1, 2, 3, 4 or 5        R^(a).

In an embodiment:

-   -   X and Y taken together form —C(O)R⁸ or —C(O)OR⁸, or    -   X is carbon and Y is oxo; and X and R⁵ taken together with the        carbon atoms to which they are attached form a carbocyclic        group, which is optionally substituted with 1, 2, 3, 4 or 5        R^(a).

In an embodiment, the compound of formula (III) is an α,β-unsaturatedcarbonyl compound.

In an embodiment, the compound of formula (III) is an enone. In aparticular embodiment, the compound of formula (III) is a cyclic enone,e.g. a cyclohexenone or a cyclopentenone. In an embodiment, the compoundof formula (III) is cyclohexen-2-one or cyclopenten-2-one, either ofwhich is optionally substituted with 1, 2, 3, 4 or 5 R^(a).

In an embodiment, the compound of formula (III) is a dienone. In anembodiment, the compound of formula (III) is a steroid compound. In anembodiment, the compound of formula (III) is a steroid compoundcomprising a dienone group.

In an embodiment, each R^(a) is independently selected from acyl,alkoxy, alkoxycarbonyl, alkylamino, alkylsulfinyl, alkylsulfonyl,alkylthio, amino, aminoalkyl, aralkyl, cyano, dialkylamino, halo,haloalkoxy, haloalkyl, hydroxy, formyl, nitro, alkyl (optionallysubstituted with e.g. alkoxy, hydroxy, haloalkoxy, halogen orhaloalkyl), aryl (optionally substituted with e.g. alkoxy, hydroxy,haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionallysubstituted with e.g. alkoxy, hydroxy, haloalkoxy, halogen, alkyl orhaloalkyl), heterocycloalkyl (optionally substituted with e.g. alkoxy,hydroxy, haloalkoxy, halogen, alkyl or haloalkyl), aminoacyl,aminosulfonyl, acylamino, sulfonylamino, heteroarylalkyl, aryloxy,heteroaryloxy, arylalkyloxy and heteroarylalkyloxy.

The hydrometallated compound undergoes an asymmetric 1,4-conjugateaddition reaction with the second compound, forming a chiral compound ina stereoisomeric excess. This reaction occurs in the presence ofcatalytic complex of the present invention. Thus, for instance, thecompound of formula (II) and the compound of formula (III) may bereacted in the presence of a catalytic complex of the present invention,to form a compound of formula (IV) in a stereoisomeric excess. Whilstthe first and second compounds will normally be separate compounds, itis envisaged that the processes described herein may also be performedintramolecularly, i.e. using a compound which is capable of beinghydrometallated and, moreover, which is capable of undergoing anintramolecular asymmetric 1,4-conjugate addition reaction.

In another embodiment, the present invention provides a process forproducing a chiral compound of the formula (IVa) in a stereoisomericexcess:

-   -   wherein        -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined above in            relation to formula (IV); and        -   R¹⁵ and R¹⁶ are each independently selected from hydrogen,            R^(a), hydrocarbyl optionally substituted with 1, 2, 3, 4 or            5 R^(a); and —(CH₂)_(j)-heterocyclyl optionally substituted            with 1, 2, 3, 4 or 5 R^(a);        -   R^(a) and j are as defined above in relation to formula            (IV); and        -   the asterisk * designates a chiral centre of (R) or (S)            configuration.

The compound of formula (IVa) may be obtained by first contacting acompound comprising an alkene bond with a hydrometallating agent of theformula HM, wherein M comprises a metal (e.g. a transition metal),wherein said compound and the hydrometallating agent are contacted underconditions such that the compounds react to form a compound of theformula (II):

Thus, for instance, the process may comprise contacting an alkenecompound of the formula (I):

with a hydrometallating agent of the formula HM under conditions suchthat the compounds react to form the compound of formula (II).

The compound of the formula (II) is then contacted with a compound ofthe formula (III):

and a compound of the formula (VII):

wherein the compound of formula (II), the compound of formula (III) andthe compound of formula (VII) are contacted under conditions such thatthey undergo an asymmetric 1,4-conjugate addition reaction to form astereoisomeric excess of a compound of formula (IVa), wherein saidasymmetric conjugate addition reaction is performed in the presence of acatalytic complex of the present invention.

The compound comprising an alkene bond, the compound of formula (III),the hydrometallating agent, the catalytic complex and the non-racemicchiral ligand may be as defined in any of the embodiments describedabove in relation to processes for the production of compounds of theformula (IV).

In embodiments, R⁷ is hydrogen. In embodiments, R¹⁵ is hydrogen and/orR¹⁶ is hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R^(a),e.g. alkyl or -alkyl-aryl optionally substituted with 1, 2, 3, 4 or 5R^(a)

In another embodiment, the hydrometallated first compound and the secondcompound are contacted under conditions such that they undergo anasymmetric 1,6-conjugate addition reaction to form a chiral compound.Thus, a carbon atom of said hydrometallated first compound to which themetal is attached may bind to the carbon atom at said 6-position of thesecond compound, forming a stereoisomeric excess of a compound having achiral carbon atom at said 6-position.

Accordingly, in one embodiment, the process comprises:

-   -   (i) contacting a first compound comprising an alkene bond with a        hydrometallating agent, wherein the first compound and the        hydrometallating agent are contacted under conditions such that        the first compound is hydrometallated by said hydrometallating        agent; and    -   (ii) contacting the hydrometallated first compound with a second        compound, wherein the second compound comprises a conjugated        π-bond system which is capable of undergoing a 1,6-conjugate        addition reaction and which has a carbon atom at said        6-position, wherein the hydrometallated first compound and the        second compound are contacted under conditions such that they        undergo an asymmetric 1,6-conjugate addition reaction in which a        carbon atom of said hydrometallated first compound binds to the        carbon atom at said 6-position of the second compound, forming a        stereoisomeric excess of a compound having a chiral carbon atom        at said 6-position, wherein said asymmetric conjugate addition        reaction is performed in the presence of a catalytic complex of        the present invention.

In an embodiment, the asymmetric conjugate addition reaction results inthe formation of a quaternary centre at the 6-position.

In a particular embodiment, the present invention provides a process forproducing a chiral compound of the formula (VI) in a stereoisomericexcess (e.g. an enantiomeric or diastereomeric excess):

-   -   wherein        -   R¹, R², R³ and R⁴ are each independently selected from            hydrogen, R^(a), hydrocarbyl optionally substituted with 1,            2, 3, 4 or 5 R^(a); and —(CH₂)_(j)-heterocyclyl optionally            substituted with 1, 2, 3, 4 or 5 R^(a);        -   or R¹ and R³ taken together with the carbon atoms to which            they are attached may form a carbocyclic or heterocyclic            group, which group is optionally substituted with 1, 2, 3, 4            or 5 R^(a);        -   R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are each independently selected            from hydrogen, R^(a), hydrocarbyl optionally substituted            with 1, 2, 3, 4 or 5 R^(a); and —(CH₂)_(j)-heterocyclyl            optionally substituted with 1, 2, 3, 4 or 5 R^(a);        -   or two or more (e.g. two or three) of R¹⁰, R¹¹, R¹², R¹³,            R¹⁴ and X taken together with the carbon atoms to which they            are attached, may form a carbocyclic or heterocyclic group,            which group is optionally substituted with 1, 2, 3, 4 or 5            R^(a),        -   X and Y taken together form an electron withdrawing group in            which the bond between X and Y is a π-bond,        -   each R^(a) is independently selected from halogen,            trifluoromethyl, cyano, nitro, oxo, ═NR^(b), —OR^(b),            —C(O)R^(b), —C(O)N(R^(b))R^(c), —C(O)OR^(b), —C(O)SR^(b),            —C(O)SeR^(b), —OC(O)R^(b), —S(O)_(k)R^(b),            —S(O)_(k)N(R^(b))R^(c), —N(R^(b))R^(c),            —N(R^(b))N(R^(b))R^(c), —N(R^(b))C(O)R^(c) and            —N(R^(b))S(O)_(k)R^(b),        -   R^(b) and R^(c) are each independently hydrogen or selected            from hydrocarbyl and —(CH₂)_(j)-heterocyclyl, either of            which is optionally substituted with 1, 2, 3, 4 or 5            substituents independently selected from halogen, oxo,            cyano, amino, hydroxy, alkyl and alkoxy;        -   j is 0, 1, 2, 3, 4, 5 or 6;        -   k is 0, 1 or 2; and        -   the asterisk * designates a chiral centre of (R) or (S)            configuration.

The compound of formula (VI) may be obtained by first contacting acompound comprising an alkene bond with a hydrometallating agent of theformula HM, wherein M comprises a metal (e.g. a transition metal),wherein said compound and the hydrometallating agent are contacted underconditions such that the compounds react to form a compound of theformula (II):

Thus, for instance, the process may comprise contacting an alkenecompound of the formula (I):

with a hydrometallating agent of the formula HM under conditions suchthat the compounds react to form the compound of formula (II).

The compound of the formula (II) is then contacted with a compound ofthe formula (V):

wherein the compound of formula (II) and the compound of formula (V) arecontacted under conditions such that they undergo an asymmetric1,6-conjugate addition reaction in which a stereoisomeric excess of acompound of formula (VI) is formed. The conjugate addition reaction isperformed in the presence of a catalytic complex of the presentinvention.

In embodiments, one or more of the following may apply: (i) R¹ ishydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R^(a); (ii) R¹is alkyl, cycloalkyl or aralkyl, any of which is optionally substitutedwith 1, 2, 3, 4 or 5 R^(a); (iii) R³ is hydrogen or hydrocarbyloptionally substituted with 1, 2, 3, 4 or 5 R^(a); (iv) R³ is hydrogenor alkyl optionally substituted with 1, 2, 3, 4 or 5 R^(a); (v) R¹ andR³ taken together with the carbon atoms to which they are attached form,in the compounds of formulae (II) and (IV), cycloalkyl optionallysubstituted with 1, 2, 3, 4 or 5 R^(a); and (vi) R² and R⁴ are eachhydrogen.

In an embodiment, M comprises a metal selected from zirconium, titanium,hafnium, niobium, tantalum, boron, aluminium, tin, silicon, magnesium,zinc, palladium, iridium, copper, rhodium, ruthenium, platinum, rheniumand nickel. Preferably, M comprises a transition metal.

More preferably, the compound of formula (II) is obtained byhydrozirconation of the compound comprising said alkene bond, e.g. byhydrozirconation of a compound of the formula (I). Thus, in a preferredembodiment, the hydrometallating agent HM comprises zirconium.Preferably, the hydrometallating agent is a zirconium complex of theformula HZrR₂X as defined above. In a preferred embodiment, thehydrometallating agent is a zirconium complex of the formula HZrCp₂X asdefined above. Particularly preferred is a zirconium complex of theformula HZrCp₂Cl (the Schwartz reagent).

In embodiments, one or more of the following may apply: (i) R¹⁰ ishydrogen or hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5R^(a); (ii) R¹⁰ is hydrogen or alkyl optionally substituted with 1, 2,3, 4 or 5 R^(a); (iii) R¹¹ is hydrogen or hydrocarbyl optionallysubstituted with 1, 2, 3, 4 or 5 R^(a); (iv) R¹¹ is hydrogen or alkyloptionally substituted with 1, 2, 3, 4 or 5 R^(a); (v) R¹² is hydrogenor hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R^(a); (vi)R¹³ is hydrogen or alkyl optionally substituted with 1, 2, 3, 4 or 5R^(a); (vii) R¹⁴ is hydrogen or hydrocarbyl optionally substituted with1, 2, 3, 4 or 5 R^(a); and (viii) R¹⁴ is hydrogen or alkyl optionallysubstituted with 1, 2, 3, 4 or 5 R^(a).

In an embodiment, X and Y taken together form —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R⁹, —CN, —C(O)SR⁸, —C(O)SeR⁸, —SO₂R⁸, —SO₂NR⁸R⁹ or —NO₂, whereinR⁸ and R⁹ are each independently hydrogen or selected from hydrocarbyland —(CH₂)_(j)-heterocyclyl, either of which is optionally substitutedwith 1, 2, 3, 4 or 5 substituents independently selected from halogen,oxo, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy.

In an embodiment, X and Y taken together form —C(O)R⁸ or —C(O)OR⁸.

In an embodiment, X is carbon and Y is oxo; and X and one or more (e.g.one or two) of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ taken together with the carbonatoms to which they are attached form a carbocyclic or heterocyclicgroup, either of which is optionally substituted with 1, 2, 3, 4 or 5R^(a). In an embodiment, said carbocyclic or heterocyclic group is amulticyclic group, e.g. comprising 2, 3, 4 or 5 rings. In an embodiment,the compound of formula (V) is a steroid compound.

In an embodiment, each R^(a) is independently selected from acyl,alkoxy, alkoxycarbonyl, alkylamino, alkylsulfinyl, alkylsulfonyl,alkylthio, amino, aminoalkyl, aralkyl, cyano, dialkylamino, halo,haloalkoxy, haloalkyl, hydroxy, formyl, nitro, alkyl (optionallysubstituted with e.g. alkoxy, hydroxy, haloalkoxy, halogen orhaloalkyl), aryl (optionally substituted with e.g. alkoxy, hydroxy,haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionallysubstituted with e.g. alkoxy, hydroxy, haloalkoxy, halogen, alkyl orhaloalkyl), heterocycloalkyl (optionally substituted with e.g. alkoxy,hydroxy, haloalkoxy, halogen, alkyl or haloalkyl), aminoacyl,aminosulfonyl, acylamino, sulfonylamino, heteroarylalkyl, aryloxy,heteroaryloxy, arylalkyloxy and heteroarylalkyloxy.

The hydrometallated compound undergoes an asymmetric 1,6-conjugateaddition reaction with a second compound, forming a chiral compound in astereoisomeric excess. This reaction occurs in the presence of acatalytic complex of the present invention. Thus, for instance, thecompound of formula (II) and the compound of formula (V) may be reactedin the presence of a catalytic complex of the present invention, to forma compound of formula (VI) in a stereoisomeric excess. Whilst the firstand second compounds will normally be separate compounds, it isenvisaged that the processes described herein may also be performedintramolecularly, i.e. using a compound which is capable of beinghydrometallated and, moreover, which is capable of undergoing anintramolecular asymmetric 1,6-conjugate addition reaction.

Where the stereoselective processes of the present invention involvemore than one synthetic step, the processes may be performed in separatereaction vessels or in the same reaction vessel (i.e. as a “one-pot”reaction). A process of the present invention may comprise isolatingand/or characterising one or more intermediates, e.g. thehydrometallated alkene, of the process.

The present processes will typically be conducted in the presence of oneor more solvents. Examples of suitable solvents include dichloromethane,1,2-dichloroethane, chloroform, Et₂O, t-BuOMe, i-Pr₂O,2,2-dimethoxypropane, tetrahydrofuran, 2-methyltetrahydrofuran, diglyme,1,4-dioxane, toluene, m-xylene and hexane. In an embodiment, the processis performed in the presence of toluene or t-BuOMe. Particularly whenthe catalytic complex comprises triflimide as a counterion, it ispreferred that the process is performed in the presence of t-BuOMe.

In some instances, it may be necessary to include additional reagents inthe reaction to promote reactivity of, for example, the catalyticcomplex or other components of the reaction, in order to optimise theyield and/or enantioselectivity of the reaction. In particular, it maybe advantageous to include one or more additives such as trimethylsilylchloride (TMSCl).

By way of illustration, a process of the present invention may beconducted in accordance with one of the procedures described in theExamples or elsewhere herein. It will be understood that the processesdescribed in the Examples are solely for the purpose of illustrating theinvention and should not be construed as limiting. A process utilisingsimilar or analogous reagents and/or conditions known to one skilled inthe art may also be used to obtain a compound of the invention. Anymixtures of final products or intermediates obtained can be separated onthe basis of the physico-chemical differences of the constituents, in aknown manner, into the pure final products or intermediates, for exampleby chromatography, distillation, fractional crystallisation, or by theformation of a salt if appropriate or possible under the circumstances.

The present processes produce a chiral compound (e.g. the compound offormula (IV), the compound of formula (IVa) or the compound of formula(VI)) in a stereoisomeric excess, i.e. such that the concentration ofone stereoisomer of the chiral compound exceeds the concentration ofanother stereoisomer. That is, the present processes yield a chiralcompound with a stereoisomeric excess of greater than zero. Preferably,the present processes yield a product with a stereoisomeric excess ofgreater than 20%, greater than 50%, greater than 70%, greater than 80%,or greater than 90%. The chiral compound may be enantiomeric ordiastereomeric. For instance, the desired compound may be obtained in asubstantially pure form (e.g. a form having a purity of greater than 80%purity, in particular greater than 90%, 95% or 99%) of a singleenantiomer or diastereomer. In an embodiment, the chiral compound isenantiomeric. All stereoisomers are included within the scope of thepresent invention. Where a single enantiomer or diastereoisomer isdisclosed, the present invention also extends to the other enantiomersor diastereoisomers.

Stereoisomers may be isolated by separation of a racemic or othermixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation, or by derivatisation, for example with a homochiral acidfollowed by separation of the stereoisomers by conventional means (e.g.HPLC, chromatography over silica).

Compounds of the present invention may also exhibit geometricalisomerism. The present invention contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond and designates suchisomers as of the Z or E configuration, wherein the term “Z” representssubstituents on the same side of the carbon-carbon double bond and theterm “E” represents substituents on opposite sides of the carbon-carbondouble bond.

Compounds of the present invention (especially those containingheteroatoms and conjugated bonds) may also exist in tautomeric forms,and all such tautomers are included in the scope of the presentinvention. In particular, the present compounds (e.g. the compounds ofthe formula (IV), the compounds of formula (IVa) or the compounds offormula (VI)) may be obtained and isolated in the form of enolates andother tautomeric forms; once again, all such tautomeric forms areincluded within the scope of the present invention. The presentinvention also extends to all other variant forms of the definedcompounds, for example salts, esters, acids or other variants of thepresent compounds and their tautomers.

The present processes are particularly relevant to industry. A processof the invention may further comprise formulating a product comprisingthe chiral compound or converting the chiral compound into a product. Inan embodiment, the product is a pharmaceutical product, a cosmeticproduct, a fragrance, a foodstuff, a petrochemical product or a polymerproduct.

In particular, the present processes may be utilised in the productionof active pharmaceutical ingredients, e.g. prostaglandins. Thus, thechiral compound may be formulated together with one or morepharmaceutically acceptable carriers or excipients, to provide apharmaceutical formulation; or chemically converted to apharmaceutically active ingredient. Moreover, where the chiral compoundis an active pharmaceutical ingredient, the compound may be obtained inthe form of a free acid or base, or in the form of a pharmaceuticallyacceptable salt thereof. The term “pharmaceutically acceptable salt”refers to acid addition salts or base addition salts of the compounds inthe present invention. Pharmaceutically acceptable salts include saltsof both inorganic and organic acids.

The following non-limiting Examples illustrate the present invention.

EXAMPLES Materials and Methods

Materials

Phosphoramidite ligands were synthesised as described below. Thephosphoramidite ligands A, B and C used in the experiments of Example 4have the following structures:

Ligands A and B were commercially available (see also Teichert et al,Angew. Chem. Int. Ed., 2010, 49, 2486-2528). Ligand C was preparedaccording to the procedures set forth in Examples 1 and 2 below.

Unless stated otherwise, commercially available reagents were purchasedfrom Sigma-Aldrich, Fisher Scientific, Apollo Scientific, AcrosOrganics, Strem Chemicals, Alfa Aesar or TCI UK and were used withoutpurification. Petroleum ether refers to light petroleum boiling in therange 40-60° C. TMSCl was distilled before use and stored in Schlenkflasks under an argon atmosphere. Deuterated solvents were purchasedfrom Sigma-Aldrich (CD₂Cl₂, CDCl₃). The Schwartz reagent was preparedaccording to a literature procedure (see Buchwald et al, Org. Synth.,1993, 71, 77-82) from Cp₂ZrCl₂ provided by Strem Chemicals.(CuOTf)₂.C₆H₆ was synthesised using a modified literature procedure (seeSalomon et al, J. Am. Chem. Soc., 1973, 95(6), 1889-1897) and carefullymaintained under an inert atmosphere. (CuOTf)₂.C₆H₆ was a white oroff-white powder, not green or brown. Certain enone substrates weresynthesised according to literature procedures (see Martin et al, J. Am.Chem. Soc., 2006, 128(41), 13368-13369; and Vuagnoux-d'Augustin et al,Chem. Eur. J., 2007, 13(34), 9647-9662).

Dry THF, CH₂Cl₂, Et₂O, PhMe, benzene, hexane, DME were collected freshfrom an mBraun SPS-800 solvent purification system having been passedthrough anhydrous alumina columns. Dry tert-butyl methyl ether and2-Me-THF were purchased from Acros with an AcroSeal®. All other drysolvents used were dried over 3 Å molecular sieves and stored underargon. All other solvents were used as purchased from Sigma Aldrich,Rathburn or Fisher Scientific. 1,2-Dichloroethane was distilled beforeuse.

Methods

Procedures using oxygen- and/or moisture-sensitive materials wereperformed with anhydrous solvents under an atmosphere of anhydrous argonin flame-dried flasks, using standard Schlenk techniques. Analyticalthin-layer chromatography was performed on precoated glass-backed plates(Silica Gel 60 F₂₅₄; Merck), and visualised using a combination of UVlight (254 nm) and aqueous ceric ammonium molybdate (CAM), aqueous basicpotassium permanganate stains or vanillin solution. Flash columnchromatography was carried out using Apollo Scientific silica gel 60(0.040-0.063 nm), Merck 60 Å silica gel, VWR (40-63 μm) silica gel,Sigma Aldrich silica gel. Pressure was applied at the column head viahand bellows or a flow of nitrogen with a solvent system.

Cooling of reaction mixtures to 0° C. was achieved using an ice-waterbath. Other temperatures were obtained using a Julabo FT902 immersioncooler.

Unless stated otherwise, solution NMR spectra were recorded at roomtemperature. ¹H and ¹³C nuclear magnetic resonance experiments werecarried out using Bruker DPX-200 (200/50 MHz), AVN-400 (400/100 MHz),DQX-400 (400/100 MHz) or AVC-500 (500/125 MHz) spectrometers. Chemicalshifts are reported in ppm from the residual solvent peak. Chemicalshifts (δ) are given in ppm and coupling constants (J) are quoted inhertz (Hz). Resonances are described as s (singlet), d (doublet), t(triplet), q (quartet) and m (multiplet). Labels H and H′ refer todiastereotopic protons attached to the same carbon and impart nostereochemical information. Assignments were made with the assistance ofgCOSY, DEPT-135, gHSQC and gHMBC or gHMQC NMR spectra.

Low-resolution mass spectra were recorded using a Walters LCT premierXE. High resolution mass spectra (EI and ESI) were recorded using aBruker MicroTOF spectrometer.

Infrared measurements (neat, thin film) were carried out using a BrukerTensor 27 FT-IR with internal calibration in the range 4000-600 cm⁻¹.

Optical rotations were recorded using a Perkin-Elmer 241 Polarimeter.

Solutions were filtered using syringe filters PTFE (0.2 μm, 13 mmdiameter) from Camlab.

Racemic products were prepared by adding Cp₂ZrHCl (206 mg, 0.80 mmol,2.0 eq) to a stirred, room temperature, solution of alkene (1.0 mmol,2.5 eq) in CH₂Cl₂ (2.0 mL) under an argon atmosphere. After stirring forabout 40 min, CuBr.Me₂S (82 mg, 0.40 mmol 1.0 eq), was added to thereaction mixture and the resulting black mixture was allowed to stir foran additional 10 min before a cyclic enone (0.40 mmol, 1.0 eq) was addedvia syringe over about 1 min. Stirring at room temperature was continuedarbitrarily for 15 h before the reaction was quenched by the addition ofEt₂O (ca 3 mL) and then NH₄Cl (1M aq., ca 1.5 mL). The mixture waspartitioned between water and Et₂O and the aqueous phase extracted withEt₂O (3×10 mL). The combined organic phase was washed with NaHCO₃ (aq.sat., ca 10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo togive an oil. Flash column chromatography of the residue (EtOAc/petrol;SiO₂) gave the desired cyclic ketone.

In some instances, enantiomeric excess (ee) was determined by HPLCanalysis. Chiral HPLC separations were achieved using an Agilent 1230Infinity series normal phase HPLC unit and HP Chemstation software.Chiralpak® columns (250×4.6 mm), fitted with matching Chiralpak® GuardCartridges (10×4 mm), were used as specified in the text. Solvents usedwere of HPLC grade (Fisher Scientific, Sigma Aldrich or Rathburn); alleluent systems were isocratic.

In other instances, enantiomeric excess was determined by derivatisationof cyclic ketones. Crude material from the 1,4-addition was transferredto a vial with CDCl₃ and 3 Å molecular sieves.(+)-(R,R)-1,2-diphenylethylenediamine ((+)-(R,R)-DPEN ca. 2 eq.) wasadded and the vial was shaken and allowed to stand overnight before themixture was filtered through a glass pipette containing a small cottonplug and transferred to a NMR tube. ¹³C NMR spectroscopy (500 MHz, 1024scans) and comparison with racemic material was used to determine theenantiomeric excess.

The stereochemical configuration of compound 3b was assigned accordingto Palais et al (Chem. Eur. J., 2009, 15(40), 10473-10485) and bynon-racemic chiral GC analysis using a LIPODEX E (Macherey-Nagels)column. The stereochemical configuration of compound 3c was assignedaccording to Lee et al (J. Am. Chem. Soc., 2006, 128, 7182). Theconfiguration of compound 3e was assigned according to Palais et al. Inthe case of compounds 3a, 3d, 3f-3q, 4-6, 7a and 7b, absoluteconfigurations were assigned by analogy to compound 3b.

Deprotection of alcohols was performed by dissolving 24.5 mg (0.06 mmol,1.0 eq) in THF (1.0 mL) at room temperature and TBAF.3H₂O (1M, solutionin THF, 0.12 mL, 0.12 mmol, 2.0 eq) was added and the reaction mixturewas stirred until starting material disappearance (TLC control 9:1Petrol: EtOAc). Et₂O (2 mL) and saturated brine (1 mL) were added. Themixture was partitioned between the aqueous and Et₂O layers and theaqueous phase extracted with Et₂O (3×2 mL). The combined organic phasewas dried (Na₂SO₄), filtered and concentrated in vacuo. The obtainedalcohol was analysed by HPLC analysis.

Example 1 N-Benzhydrylpropan-2-amine

Acetone (1.9 mL, 2.58 mmol, 2.00 eq) was added to a stirring solution ofdiphenylmethanamine (2.26 mL, 12.9 mmol, 1 eq) in THF (100 mL) at roomtemperature. After 5 minutes, NaB(OAc)₃H (4.10 g, 19.4 mmol, 1.5 eq) wasadded. The resulting suspension was stirred for 48 hours. Et₂O (50 mL)and NaHCO₃ (aq. sat., ca. 50 mL) were added to the suspension which wasstirred for an extra 15 minutes. The mixture was partitioned between theaqueous and Et₂O layers and the aqueous phase extracted with Et₂O (3×30mL). The combined organic phase was concentrated in vacuo to one thirdof its volume (˜20 mL). Then HCl (aq 2.0 M, 25 mL) was added dropwise.The mixture was partitioned between the aqueous and Et₂O layers and theorganic phase extracted with HCl (aq 2.0 M, 25 mL). Then CH₂Cl₂ (20 mL)was added to the combined aqueous phases and NaOH (aq, 25%) was addeduntil the mixture became basic (pH paper, pH ˜14). The mixture waspartitioned between the aqueous and CH₂Cl₂ layers and the aqueous phaseextracted with CH₂Cl₂ (3×30 mL). The combined organic phase was dried(MgSO₄), filtered and concentrated in vacuo to afford the desiredN-benzhydrylpropan-2-amine (1.91 g, 8.45 mmol, 65%). The amine was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 1.11 (d,J=6.4 Hz, 6 H), 1.37-1.67 (m, 1 H), 2.77 (spt, J=6.3 Hz, 1 H), 5.00 (s,1 H), 7.22 (br. tt, J=7.3, 1.2 Hz, 2 H), 7.32 (br. t, J=7.6 Hz, 4 H),7.41 (br. d, J=7.3 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 23.1 (2C), 42.6, 64.2, 126.8 (2 C), 127.3 (4C), 128.3 (4 C), 144.48 (2C). MS(ESI) m/z [M+H]⁺: 226.2 (100). IR (v_(max)/cm⁻¹): 700, 1028, 1167, 1493,2960.

Example 2N-Benzhydryl-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxa-phosphepin-4-amine(ligand C)

Triethylamine (4.6 mL, 33.3 mmol, 5.00 eq) was added dropwise to an ice-cooled solution of PCl₃ (0.58 mL, 6.66 mmol, 1.00 eq) in CH₂Cl₂ (40mL). The ice bath was removed and the solution left to warm to roomtemperature before N-benzhydrylpropan-2-amine (1.5 g, 6.33 mmol, 1.00eq) was added to the stirring solution. (R)-Binaphthol was added to thesuspension after 5 hours and the subsequent mixture was left stirringovernight. The solution was then filtered on a small pad of silica andCelite® and washed with CH₂Cl₂. After removing the solvent in vacuo,flash column chromatography of the yellow residue (78:17:1: Petrol:CH₂Cl₂/Et₃N; SiO₂) gave phosphoramidite ligand C (2.61 g, 4.8 mmol, 73%)as a white solid. ¹H NMR (500 MHz, CDCl₃) δ_(H)/ppm 1.06 (d, J=6.6 Hz, 3H), 1.18 (d, J=6.1 Hz, 3 H), 3.68 (dq, J=11.8, 6.1 Hz, 1 H), 5.80 (d,J=17.0 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.28-7.46 (m, 11 H), 7.50 (q, J=7.6Hz, 4 H), 7.58 (d, J=7.6 Hz, 2 H), 7.86 (d, J=8.8 Hz, 1 H), 7.94 (d,J=7.6 Hz, 2 H), 7.98 (d, J=8.8 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃)δ_(C)/ppm 23.0, 23.2, 46.8, 60.6, 60.8, 121.6, 122.1, 122.3, 124.0,124.3, 124.6, 125, 125.9, 126.96, 127.00 (3 C), 127.1, 128.1 (3 C),128.2 (2 C), 128.2, 128.3 (3 C), 128.7 (2 C), 129.0 (2 C), 129.3, 130.1,130.4, 131.3, 132.7, 143.3, 143.5, 149.1, 150.4. ³¹P NMR (200 MHz CDCl₃)δ_(P)/ppm 150.64. HMRS (EI) m/z calcd for C₃₆H₃₀NO₂P [M]⁺: 539.2014found: 539.2018. [α]²⁰ ₅₈₉=−175.88 (c 1.06, CHCl₃). IR (v_(max)/cm⁻¹):747, 982, 1250, 1590, 3060.

Example 3 Triflimide Complex Containing Ligand C

To a flame dried Schlenk flask, at room temperature under an argonatmosphere was added CuCl (46 mg, 0.47 mmol, 1 eq.) and ligand C (253mg, 0.47 mmol, 1.0 eq.) followed by CH₂Cl₂ (10 mL). This mixture wasstirred for 1 h before AgNTf₂ (200 mg, 0.52 mmol, 1.1 eq) was added tothe clear solution and stirred for a further 20 min. On the addition ofthe AgNTf₂ the solution turns grey and a precipitate is formed (AgCl).The resulting solution was cannula filtrated into another Schlenk flask.The solvent was then gently removed by use of an oil-pump vacuum (withliquid nitrogen trapping). The resulting off-white solid was dried forat least one extra hour under oil-pump vacuum before storing thecatalyst complex under argon. ¹H NMR (400 MHz, C₆D₆) δ_(H)/ppm 7.86 (d,J=8.8 Hz, 1 H), 7.71 (d, J=8.8 Hz, 1 H), 7.52-7.65 (m, 3 H), 7.28-7.45(m, 9 H), 7.24 (d, J=8.5 Hz, 2 H), 7.17-7.22 (m, 2 H), 7.02-7.12 (m, 2H), 6.85 (dt, J=23.0, 8.0 Hz, 2 H), 5.38-5.54 (m, 1 H), 3.38-3.53 (m, 1H), 0.74 (d, J=6.9 Hz, 3 H), 0.60 (d, J=6.6 Hz, 3 H). ¹³C NMR (125 MHz,C₆D₆) δ_(C)/ppm 148.6 (d, J=12.4 Hz), 147.9 (d, J=4.8 Hz), 141.7 (d,J=6.7 Hz), 141.2 (d, J=8.6 Hz), 132.9, 132.7, 132.6, 132.6, 131.5,130.6, 130.5, 130.3, 129.2, 129.1, 129.0, 127.3, 127.3 (2C), 127.1,127.0, 127.0, 126.9, 126.0, 125.9, 123.2, 123.1, 122.1, 122.1, 121.5,121.4, 120.8 (2C), 120.0 (q, J=323 Hz, 2C), 61.0 (d, J=23.0 Hz), 48.8(d, J=4.8 Hz), 22.1, 22.0. ¹⁹F NMR (470 MHz, C₆D₆) δ_(F)/ppm −76.0 (s,6F). ³¹P NMR (200 MHz, C₆D₆) δ_(P)/ppm 121.59 (br. s, 1P). HRMS (EI) m/zcalcd for C₃₈H₃₀CuF₆N₂O₆PS₂ [M]⁺: 882.0483, found: 882.0455. [α]²⁴₅₈₉=−98.79 (c 1.00, CHCl₃). IR (v_(max)/cm⁻¹): 834, 950, 1060, 1133,1197, 1325.

Example 4

The coupling of 4-phenyl-1-butene and 3-methyl-2-cyclohexen-1-one wasevaluated:

Hydrometallation of 1 with the Schwartz reagent (Cp₂ZrHCl) provided analkylzirconium species that reacted with 2 in the presence of aphosphoramidite ligand and a copper source to give 3. Variousphosphoramidite ligands, sources of copper, additives and solvents wereexamined. Enantiomeric excess (ee) was determined by HPLC analysis.

The following general procedure was used. Copper source (5.0 mg, 0.01mmol, 0.05 eq) and the phosphoramidite ligand (10.7 mg, 0.02 mmol, 0.1eq) were dissolved in the reaction solvent (1.0 mL) under an argonatmosphere and allowed to stir for 1 h at room temperature. In anotherflask, Cp₂ZrHCl (103.0 mg, 0.40 mmol, 2.0 eq) was added to a stirred,room temperature, solution of 4-phenyl-1-butene (0.08 mL, 0.5 mmol, 2.5eq) in CH₂Cl₂ (0.20 mL) under an argon atmosphere. After stirring forabout 40 min, the resulting clear yellow solution was transferred viasyringe over about 1 min to the stirred solution containing the copperand ligand under an argon atmosphere. The resulting dark mixture wasallowed to stir for an additional 10 min before 3-methyl-2-cyclohexenone(23 μL, 0.20 mmol, 1.0 eq) was added dropwise via syringe. The reactionwas stirred overnight and was quenched by the addition of Et₂O (ca 3 mL)and then NH₄Cl (1 M aq., ca 1.5 mL). The mixture was partitioned betweenwater and Et₂O and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 10 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to give an oil. Flashcolumn chromatography of the residue (EtOAc/petrol; SiO₂) gave thedesired cyclic ketone.

The results of this experiment are presented in Table 1. Absolutestereochemical configurations were assigned by analogy to compounds 3band 3o.

TABLE 1 En- Li- Addi- ee try Copper Source gand tive Solvent R/S (%) 1(CuOTf)₂•PhH A TMSCl Et₂O S 60 2 (CuOTf)₂•PhH B TMSCl Et₂O R 70 3(CuOTf)₂•PhH C TMSCl Et₂O R 61 4 [Cu(MeCN)₄]•BF₄ B TMSCl Et₂O R 23 5CuCl + AgNTf₂ B TMSCl Et₂O R 82 6 CuCl + AgNTf₂ B — Et₂O R 88 7 CuCl +AgSbF₆ B — CH₂Cl₂ R 73 8 CuCl + AgClO₄ B — CH₂Cl₂ R 69 9 CuCl + AgNTf₂ B— CH₂Cl₂ R 78 10 CuCl + AgNTf₂ C — CH₂Cl₂ R 92 11 CuCl + AgNTf₂ C —ClCH₂CH₂Cl R 90 12 CuCl + AgNTf₂ C — t-BuOMe R 94 13 CuCl + AgNTf₂ C —2-Me—THF R 90

As can be seen from Table 1, hydrometallation of 1 followed byasymmetric conjugate addition to 2 in the presence of phosphoramiditeligand A, (CuOTf)₂.PhH and TMSCl (Table 1, entry 1) gave (S)-3 in 45%yield and 60% ee. The use of diastereomeric ligand B gave (R)-3 andimproved the ee to 70% (Table 1, entry 2), while isomeric ligand C gave(R)-3 with 61% ee. Thus, ligand C provided comparable levels ofenantioselectivity to isomeric ligands A and B. Using ligand B incombination with different copper sources (Table 1, entries 4, 5, 7 and8) showed that the reaction was sensitive to the copper counterion andthat the triflimide anion provided high levels of enantioselectivity.Using ligand C in combination with copper triflimide (CuNTf₂) gaveparticularly desirable enantioselectivity in a range of differentsolvents (Table 1, entries 10-13). The lack of sensitivity of the ligandC—CuNTf₂ system to solvent effects suggested that it was robust.

Example 5 (−)-(R)-3-Methyl-3-(4-phenylbutyl)cyclohexanone (3a)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.040 mmol,0.10 eq) were dissolved in t-BuOMe (2.0 mL) under an argon atmosphereand the resulting mixture allowed to stir at room temperature. After 1hour, AgNTf₂ (23.2 mg, 0.060 mmol, 0.15 eq) was added and the suspensionwas stirred for another 15 min. In another flask, Cp₂ZrHCl (206 mg, 0.80mmol, 2.0 eq) was added to a stirred, room temperature, solution of4-phenyl-1-butene (0.15 mL, 1.0 mmol, 2.5 eq) in CH₂Cl₂ (0.40 mL) underan argon atmosphere. After stirring for 15 min, the stirred solutioncontaining the copper and ligand was transferred and filtered using asyringe filter to the clear yellow solution containing thealkene/zirconium mixture. The resulting black mixture was allowed tostir for an additional 10 min before 3-methyl-2-cyclohexenone (45 μL,0.40 mmol, 1.0 eq) was added dropwise via syringe. Stirring wascontinued for about 12 h before the reaction was quenched by theaddition of Et₂O (ca 3 mL) and then NH₄Cl (1M aq., ca 1.5 mL). Themixture was partitioned between the aqueous and Et₂O layers and theaqueous phase extracted with Et₂O (3×10 mL). The combined organic phasewas washed with NaHCO₃ (aq. sat., ca 10 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. Flash column chromatography of the yellowresidue (1:9 EtOAc/petrol; SiO₂) gave(−)-(R)-3-Methyl-3-(4-phenylbutyl)cyclohexanone 3a (65 mg, 0.27 mmol,66%) as a colourless oil. HPLC analysis indicated an enantiomeric excessof 94% [Chiralpak® IC; flow: 1 mL/min; hexane/i-PrOH: 98:2; λ=210 nm;major enantiomer (−)-(R)-3-Methyl-3-(4-phenylbutyl)cyclohexanone,t_(R)=16.8 min; major enantiomer(+)-(S)-3-Methyl-3-(4-phenylbutyl)cyclohexanone, t_(R)=17.9 min]. ¹H NMR(400 MHz, CDCl₃) δ_(H)/ppm 0.82 (s, 3 H), 1.21 (m, 4 H), 1.39-1.61 (m, 4H), 1.76 (m, 2 H), 1.97-2.05 (m, 1 H), 2.06-2.13 (m, 1 H), 2.19 (t,J=6.8 Hz, 2 H), 2.53 (br. t, J=6.8, 6.8 Hz, 2 H), 7.04-7.12 (m, 3 H),7.16-7.23 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 22.1, 23.0, 25.0,32.0, 35.8, 35.8, 38.5, 40.9, 41.4, 53.7, 125.6, 128.2 (2 C), 128.3 (2C), 142.5, 212.4. HRMS (ESI) m/z calcd for C₁₇H₂₄NaO [M+Na]⁺: 267.1719,found: 267.1715. [α]²⁰ ₅₈₉=−2.8 (c 0.92, CHCl₃). IR (v_(max)/cm⁻¹): 776,836, 1088, 1252, 1713, 2857, 2932.

Example 6 (+)-(R)-3-Ethyl-3-methylcyclohexanone (3b)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.04 mmol, 0.10eq) were dissolved in ^(t)BuOMe (2.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) wasdissolved in CH₂Cl₂ (1.0 mL) at room temperature, ethylene was thenbubbled through the solution for 2 min and the reaction was stirred for15 min under ethylene atmosphere using a balloon. The solution becameclear and yellow. AgNTf₂ (17.0 mg, 0.044 mmol, 0.11 eq) was then addedto the Cu-ligand mixture and it was stirred for 15 min and filtered viasyringe over 1 min to the hydrozirconation reaction flask. The resultingdark mixture was allowed to stir for an additional 10 min before3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0 eq) was added dropwisevia syringe. Stirring at room temperature was continued 12 h before thereaction was quenched by the addition of Et₂O (ca 6 mL) and then NH₄Cl(1 M aq., ca 3.0 mL). The mixture was partitioned between water and Et₂Oand the aqueous phase extracted with Et₂O (3×15 mL). The combinedorganic phase was washed with NaHCO₃ (aq. sat., ca 15 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9, EtOAc/petrol; SiO₂) gave(+)-(R)-3-ethyl-3-methylcyclohexanone 3b (45 mg, 0.32 mmol, 81%) as acolorless oil. Enantiomeric excess (91% ee) was determined byintegration of the diastereomeric mixture of the corresponding(+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopic analysis. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 2.26 (t, 2 H, J=6.6 Hz), 2.16 (d, 1 H, J=13.6 Hz),2.08 (d, 1H, J=13.6 Hz), 1.88-1.81 (m, 2H), 1.64-1.59 (m, 1H), 1.56-1.51(m, 1H), 1.33 (q, J=7.3 Hz, 2H), 0.88 (s, 3H), 0.83 (t, 3H, J=7.6 Hz).¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.8, 53.7, 41.4, 39.0, 35.7, 34.3,24.7, 22.5, 8.1. MS (ESI) m/z [M+Na]⁺: 163.1 (100). IR (ATR) v (cm⁻¹):1227, 1764, 2857, 2930. [α]²⁰ ₅₈₉=+5.53 (c 0.85, CHCl₃). Thestereochemical configuration of the compound was assigned based onliterature (see Palais et al, cited above) and by non-racemic chiral GCanalysis using a LIPODEX E (Macherey-Nagels) column. [Major enantiomer(+)-(R)-3-Ethyl-3-methylcyclohexanone, t_(R)=4.30 min; major enantiomer(−)-(S)-3-Ethyl-3-methylcyclohexanone, t_(R)=5.06 min].

Example 7 (+)-(R)-3-Butyl-3-methylcyclohexanone (3c)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.04 mmol, 0.10eq) were dissolved in ^(t)BuOMe (2.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) wasdissolved in CH₂Cl₂ (1.0 mL) at room temperature, 1-butene was thenbubbled through the solution for 2 min and the reaction was stirred for15 min under 1-butene atmosphere using a balloon. The solution becameclear and yellow. AgNTf₂ (17.0 mg, 0.044 mmol, 0.11 eq) was then addedto the Cu-ligand mixture and it was stirred for 15 min and filtered viasyringe over 1 min to the hydrozirconation reaction flask. The resultingdark mixture was allowed to stir for an additional 10 min before3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0 eq) was added dropwisevia syringe. Stirring at room temperature was continued 12 h before thereaction was quenched by the addition of Et₂O (ca 6 mL) and then NH₄Cl(1 M aq., ca 3.0 mL). The mixture was partitioned between water and Et₂Oand the aqueous phase extracted with Et₂O (3×15 mL). The combinedorganic phase was washed with NaHCO₃ (aq. sat., ca 15 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(+)-(R)-3-butyl-3-methylcyclohexanone 3c (53 mg, 0.31 mmol, 79%) as acolourless oil. Enantiomeric excess (89% ee) was determined byintegration of the diastereomeric mixture of the corresponding(+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopic analysis. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 2.25 (t, 2 H, J=7.2 Hz), 2.16 (d, 1 H, J=13.6 Hz),2.07 (d, 1 H, J=13.6 Hz), 1.86-1.80 (m, 2 H), 1.64-1.57 (m, 2 H),1.29-1.17 (m, 6 H), 0.90 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm212.7, 54.0, 41.4, 41.2, 38.7, 36.0, 25.7, 25.3, 23.5, 22.3, 14.2. IR(ATR) v (cm⁻¹): 1459, 1714, 2873, 2931, 2957. [α]²⁰ ₅₈₉=+0.80 (c 1.06,CHCl₃). The stereochemical configuration of the compound was assignedaccording to Lee et al (cited above).

Example 8 (−)-(S)-3-Isopentyl-3-methylcyclohexanone (3d)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.04 mmol, 0.10eq) were dissolved in ^(t)BuOMe (2.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) wasdissolved in CH₂Cl₂ (1.0 mL) at room temperature, 3-methyl-1-butene wasthen bubbled through the solution for 2 min and the reaction was stirredfor 15 min under 3-methyl-1-butene atmosphere using a balloon. Thesolution became clear and yellow. AgNTf₂ (17.0 mg, 0.044 mmol, 0.11 eq)was then added to the Cu-ligand mixture and it was stirred for 15 minand filtered via syringe over 1 min to the hydrozirconation reactionflask. The resulting dark mixture was allowed to stir for an additional10 min before 3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0 eq) wasadded dropwise via syringe. Stirring at room temperature was continued12 h before the reaction was quenched by the addition of Et₂O (ca 6 mL)and then NH₄Cl (1 M aq., ca 3.0 mL). The mixture was partitioned betweenwater and Et₂O and the aqueous phase extracted with Et₂O (3×15 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 15 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(+)-(S)-3-isopentyl-3-methylcyclohexanone 3d (55 mg, 0.30 mmol, 76%) asa colourless oil. Enantiomeric excess (94% ee) was determined byintegration of the diastereomeric mixture of the corresponding(+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopic analysis. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 2.27 (t, J=6.9 Hz, 2 H), 2.17 (d, 1 H, J=13.5 Hz),2.08 (d, 1 H, J=13.5 Hz), 1.88-1.83 (m, 2 H), 1.67-1.60 (m, 1 H),1.55-1.45 (m, 1 H), 1.47-1.41 (m, 1 H), 1.29-1.19 (m, 2 H), 1.17-1.06(m, 2 H), 0.91 (s, 3H), 0.88 (d, 6H, J=6.7 Hz). ¹³C NMR (100 MHz, CDCl₃)δ_(C)/ppm 212.8, 54.1, 41.4, 39.5, 38.8, 36.0, 32.6, 28.9, 25.4, 22.9,22.9, 22.4. MS (ESI) m/z [M+Na]⁺: 205.2. IR (ATR) v (cm⁻¹): 1466, 1713,2871, 2955. [α]²⁰ ₅₈₉=−2.51 (c 1.34, CHCl₃).

Example 9 (+)-(S)-3-Hexyl-3-methylcyclohexanone (3e)

CuCl (2.7 mg, 0.03 mmol, 0.10 eq) and ligand C (15.4 mg, 0.03 mmol, 0.10eq) were dissolved in ^(t)BuOMe (1.5 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (154 mg, 0.80 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 1-hexene (94 μL, 0.75 mmol,2.50 eq) in CH₂Cl₂ (0.40 mL) under an argon atmosphere. After 1 h thesolution became clear and yellow. AgNTf₂ (12.8 mg, 0.033 mmol, 0.11 eq)was then added to the Cu-ligand mixture and it was stirred for 10 minand filtered via syringe over 1 min to the hydrozirconation reactionflask. The resulting dark mixture was allowed to stir for an additional10 min before 3-methyl-2-cyclohexenone (33 μL, 0.30 mmol, 1.0 eq) wasadded dropwise via syringe. Stirring at room temperature was continuedfor 12 h before the reaction was quenched by the addition of Et₂O (ca 4mL) and then NH₄Cl (1 M aq., ca 2 mL). The mixture was partitionedbetween water and Et₂O and the aqueous phase extracted with Et₂O (3×12mL). The combined organic phase was washed with NaHCO₃ (aq. sat., ca 12mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(+)-(S)-3-hexyl-3-methylcyclohexanone 3e (38 mg, 0.29 mmol, 95%) as acolourless oil. Enantiomeric excess (96% ee) was determined byintegration of the diastereomeric mixture of the corresponding(+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopic analysis. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 2.25 (t, J=6.8 Hz, 2H), 2.16 (d, J=13.4 Hz, 1H),2.08 (d, J=13.4 Hz, 1H), 1.90-1.76 (m, 2H), 1.61 (dt, J=13.1, 6.4 Hz,1H), 1.56-1.46 (m, 1H), 1.34-1.15 (m, 10H), 0.87 (m, 6H). ¹³C NMR (100MHz, CDCl₃) δ_(C)/ppm 212.6, 54.0, 41.7, 41.2, 38.7, 35.9, 31.9, 30.1,25.2, 23.4, 22.8, 22.3, 14.2. HRMS (ESI) m/z calcd for C₁₃H₂₄NaO[M+Na]⁺: 219.1719, found: 219.1715. IR (ATR) v (cm⁻¹): 1459, 1712, 2856,2928. [α]²⁰ ₅₈₉=−2.42 (c 0.66, CHCl₃). The stereochemical configurationof the compound was assigned according to Palais et al, cited above.

Example 10 (−)-(R)-3-(3,3-Dimethylbutyl)-3-methylcyclohexanone (3f)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.040 mmol,0.10 eq) were dissolved in t-BuOMe (2.0 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (23.2 mg, 0.060mmol, 0.15 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) was added toa stirred, room temperature, solution of 3,3-dimethyl-1-butene (0.13 mL,1.0 mmol, 2.5 eq) in CH₂Cl₂ (0.80 mL) under an argon atmosphere andheated at 40° C. for 1 h before being cooled to room temperature oncethe hydrozirconation was complete (clear yellow solution). The stirredsolution containing the copper and ligand was transferred and filteredusing a syringe filter to the clear yellow solution. The resulting blackmixture was allowed to stir for an additional 10 min before3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0 eq) was added dropwisevia syringe. Stirring continued 12 h before the reaction was quenched bythe addition of Et₂O (ca 3 mL) and then NH₄Cl (1M aq., ca 1.5 mL). Themixture was partitioned between the aqueous and Et₂O layers and theaqueous phase extracted with Et₂O (3×10 mL). The combined organic phasewas washed with NaHCO₃ (aq. sat., ca 10 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. Flash column chromatography of the yellowresidue (1:9 EtOAc/petrol; SiO₂) afforded(−)-(R)-3-(3,3-Dimethylbutyl)-3-methylcyclohexanone 3f (38.9 mg, 0.20mmol, 50%) as a colourless oil. Enantiomeric excess (86% ee) wasdetermined by integration of the diastereomeric mixture of thecorresponding (+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopicanalysis. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 2.28 (t, J=6.8 Hz, 2 H),2.06-2.22 (m, 2 H), 1.85 (dt, J=13.0, 6.5 Hz, 2 H), 1.59-1.67 (m, 1 H),1.48-1.57 (m, 1 H), 1.19 (d, J=3.7 Hz, 2 H), 1.06-1.16 (m, 2 H), 0.90(s, 3 H), 0.86 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.5, 54.0,41.1, 38.3, 37.0, 35.7, 35.6, 30.0, 29.3 (3 C), 25.0, 22.1. HRMS (ESI)m/z calcd for C₁₃H₂₄NaO [M+Na]⁺: 219.1719 found: 219.1713. [α]²⁰₅₈₉=−3.43 (c 0.81, CHCl₃). IR (ATR) v (cm⁻¹): 1364, 1467, 1713, 2952.

Example 11 (−)-(R)-3-Methyl-3-tetradecylcyclohexanone (3g)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.040 mmol,0.10 eq) were dissolved in t-BuOMe (2.0 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (17.2 mg, 0.060mmol, 0.11 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (206.0 mg, 0.80 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 1-tetradecene (0.25 mL, 1.0mmol, 2.5 eq) in CH₂Cl₂ (0.40 mL) under an argon atmosphere. Afterstirring for 15 min, the stirred solution containing the copper andligand was transferred and filtered using a syringe filter to the clearyellow solution. The resulting black mixture was allowed to stir for anadditional 10 min before 3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0eq) was added dropwise via syringe. Stirring continued 12 h before thereaction was quenched by the addition of Et₂O (ca 3 mL) and then NH₄Cl(1M aq., ca 1.5 mL). The mixture was partitioned between the aqueous andEt₂O layers and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 10 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:19 EtOAc/petrol; SiO₂) gave(−)-(R)-3-Methyl-3-tetradecylcyclohexanone 3g (83 mg, 0.27 mmol, 67%) asa colourless oil. Enantiomeric excess (94% ee) was determined byintegration of the diastereomeric mixture of the corresponding(+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopic analysis. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 2.26 (t, J=6.8 Hz, 2 H), 2.18 (d, J=13.8 Hz, 1 H),2.09 (d, J=13.5 Hz, 1 H), 1.85 (quin, J=6.6 Hz, 2 H), 1.62 (dt, J=13.5,6.6 Hz, 1 H), 1.52 (dt, J=13.5, 6.6 Hz, 1 H), 1.19-1.31 (m, 26 H), 0.90(s, 3H), 0.87 (t, J=6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm212.4, 53.8, 41.6, 41.0, 38.6, 35.8, 31.9, 30.3, 29.48-29.79 (br. m, 7C), 29.3, 25.1, 23.3, 22.7, 22.1, 14.1. HRMS (ESI) m/z calcd forC₂₁H₄₀NaO [M+Na]⁺: 331.2971 found: 331.2974. [α]²⁰ ₅₈₉=−0.74 (c 1.00,CHCl₃). IR (ATR) v (cm⁻¹): 776, 1217, 1228, 1367, 1456, 1739, 2852,2923.

Example 12 (−)-(R)-3-Methyl-3-(4-phenylhexyl)cyclohexanone (3h)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.040 mmol,0.10 eq) were dissolved in t-BuOMe (2.0 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (23.2 mg, 0.060mmol, 0.15 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (206.0 mg, 0.80 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 6-phenyl-1-hexene (0.18 mL,1.0 mmol, 2.5 eq) in CH₂Cl₂ (0.40 mL) under an argon atmosphere. Afterstirring for 15 min, the stirred solution containing the copper andligand was transferred and filtered using a syringe filter to the clearyellow solution. The resulting black mixture was allowed to stir for anadditional 10 min before 3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0eq) was added dropwise via syringe. Stirring continued 12 h before thereaction was quenched by the addition of Et₂O (ca 3 mL) and then NH₄Cl(1M aq., ca 1.5 mL). The mixture was partitioned between the aqueous andEt₂O layers and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 10 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(−)-(R)-3-methyl-3-(4-phenylhexyl)cyclohexanone 3h (70.9 mg, 0.26 mmol,65%) as a colourless oil. HPLC analysis indicated an enantiomeric excessof 90% [Chiralpak® IC; flow: 1 mL/min; hexane/i-PrOH: 99:1; λ=210 nm;major enantiomer (−)-(R)-3-Methyl-3-(4-phenylhexyl)cyclohexanonet_(R)=19.3 min; minor enantiomer(+)-(S)-3-Methyl-3-(4-phenylhexyl)cyclohexanone, t_(R)=20.4 min]. ¹H NMR(400 MHz, CDCl₃) δ_(H)/ppm 0.83 (s, 3 H), 1.09-1.32 (m, 9 H), 1.38-1.47(m, 1 H), 1.48-1.63 (m, 4 H), 1.78 (quin, J=6.5 Hz, 2 H), 1.98-2.04 (m,1 H), 2.06-2.13 (m, 1 H), 2.19 (t, J=6.5 Hz, 2 H), 2.52 (t, J=7.6 Hz, 2H), 7.03-7.14 (m, 3 H), 7.16-7.26 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃)δ_(C)/ppm 22.1, 23.3, 25.1, 29.3, 30.2, 31.5, 35.8, 36.0, 38.6, 41.0,41.6, 53.8, 125.6, 128.2 (2 C), 128.4 (2 C), 142.8, 212.5. HRMS (ESI)m/z calcd for C₁₉H₂₈NaO [M+Na]⁺: 295.2032 found: 295.2020. [α]²⁰₅₅₉=−11.10 (c 0.91, CHCl₃). IR (v_(max)/cm⁻¹): 699, 1454, 1495, 1711,2855, 2929.

Example 13 (−)-(R)-3-(Hex-5-en-1-yl)-3-methylcyclohexanone (3i)

CuCl (1.8 mg, 0.02 mmol, 0.10 eq) and ligand C (10.8 mg, 0.02 mmol, 0.10eq) were dissolved in ^(t)BuOMe (1.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (103 mg, 0.40 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 1,5-hexadiene (238 μL, 2.00mmol, 10 eq) in CH₂Cl₂ (0.40 mL) under an argon atmosphere. After 40 minthe solution became clear and yellow. AgNTf₂ (8.5 mg, 0.022 mmol, 0.11eq) was then added to the Cu-ligand mixture and it was stirred for 10min and filtered via syringe over 1 min to the hydrozirconation reactionflask. The resulting dark mixture was allowed to stir for an additional10 min before 3-methyl-2-cyclohexenone (23 μL, 0.20 mmol, 1.0 eq) wasadded dropwise via syringe. Stirring at room temperature was continuedfor 12 h before the reaction was quenched by the addition of Et₂O (ca 3mL) and then NH₄Cl (1 M aq., ca 1.5 mL). The mixture was partitionedbetween water and Et₂O and the aqueous phase extracted with Et₂O (3×10mL). The combined organic phase was washed with NaHCO₃ (aq. sat., ca 10mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(−)-(R)-3-(Hex-5-en-1-yl)-3-methylcyclohexanone 3i (29 mg, 0.15 mmol,75%) as a colourless oil. Enantiomeric excess (78% ee) was determined byintegration of the diastereomeric mixture of the corresponding(+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopic analysis. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 5.79 (ddt, J=16.9, 10.1, 6.7 Hz, 1H), 5.05-4.88(m, 2H), 2.27 (t, J=7.0 Hz, 2H), 2.31-2.05 (m, 2H), 2.08-1.98 (m, 2H),1.85 (qd, J=7.1, 5.4 Hz, 2H), 1.69-1.48 (m, 2H), 1.41-1.31 (m, 2H),1.29-1.22 (m, 4H), 0.91 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm212.6, 139.0, 114.6, 53.9, 41.6, 41.2, 38.8, 35.9, 33.8, 29.6, 25.3,22.9, 22.3. HRMS (ESI) m/z calcd for C₁₃H₂₂NaO [M+Na]⁺: 217.1563, found:321.1558. IR (ATR) v (cm⁻¹): 1461, 1714, 2855, 2931.

Example 14 (−)-(S)-3-(2-(Cyclohex-3-en-1-yl)ethyl)-3-methylcyclohexanone(3j)

CuCl (1.8 mg, 0.02 mmol, 0.10 eq) and ligand C (10.8 mg, 0.02 mmol, 0.10eq) were dissolved in ^(t)BuOMe (1.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (103 mg, 0.40 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 4-vinyl-1-cyclohexene (65μL, 0.50 mmol, 2.50 eq) in CH₂Cl₂ (0.20 mL) under an argon atmosphere.After 40 min the solution became clear and yellow. AgNTf₂ (8.5 mg, 0.022mmol, 0.11 eq) was then added to the Cu-ligand mixture and it wasstirred for 10 min and filtered via syringe over 1 min to thehydrozirconation flask. The resulting dark mixture was allowed to stirfor an additional 10 min before 3-methyl-2-cyclohexenone (23 μL, 0.20mmol, 1.0 eq) was added dropwise via syringe. Stirring at roomtemperature was continued for 12 h before the reaction was quenched bythe addition of Et₂O (ca 3 mL) and then NH₄Cl (1 M aq., ca 1.5 mL). Themixture was partitioned between water and Et₂O and the aqueous phaseextracted with Et₂O (3×10 mL). The combined organic phase was washedwith NaHCO₃ (aq. sat., ca 10 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Flash column chromatography of the yellow residue(1:9 EtOAc/petrol; SiO₂) gave(−)-(S)-3-(2-(cyclohex-3-en-1-yl)ethyl)-3-methylcyclohexanone 3j (21 mg,0.10 mmol, 48%) as a colourless oil. Enantiomeric excess (86% ee) wasdetermined by integration of the diastereomeric mixture of thecorresponding (+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopicanalysis. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 5.74-5.56 (m, 2H), 2.28 (t,J=7.0 Hz, 2H), 2.19 (d, J=13.4 Hz, 1H), 2.12 (d, J=13.4 Hz, 1H),2.09-1.98 (m, 3H), 1.91-1.81 (m, 2H), 1.77-1.68 (m, 1H), 1.68-1.58 (m,2H), 1.56-1.49 (m, 1H), 1.49-1.37 (m, 1H), 1.34-1.14 (m, 5H), 0.91 (s,3H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.5, 127.1, 126.4, 53.9, 41.1,38.7, 38.5, 35.7, 34.1, 32.0, 30.1, 28.9, 25.2, 25.1, 22.1. HRMS (ESI)m/z calcd for C₁₅H₂₄NaO [M+Na]⁺: 243.1719, found: 247.1713. IR (ATR) v(cm⁻¹): 1456, 1712, 2920, 3021. [α]²⁰ ₅₈₉=−3.00 (c 0.83, CHCl₃).

Example 15 (−)-(R)-3-(5-Bromopentyl)-3-methylcyclohexanone (3k)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.040 mmol,0.10 eq) were dissolved in t-BuOMe (2.0 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (23.2 mg, 0.060mmol, 0.15 eq) was added and the suspension was stirred for another 15mins. In another flask, Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 5-bromo-1-pentene (0.12 mL,1.0 mmol, 2.5 eq) in CH₂Cl₂ (0.40 mL) under an argon atmosphere. Afterstirring for 15 min, the stirred solution containing the copper andligand was transferred and filtered using a syringe filter to the clearyellow solution. The resulting black mixture was allowed to stir for anadditional 10 min before 3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0eq) was added dropwise via syringe. Stirring continued 12 h before thereaction was quenched by the addition of Et₂O (ca 3 mL) and then NH₄Cl(1M aq., ca 1.5 mL). The mixture was partitioned between the aqueous andEt₂O layers and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 10 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂)(−)-(R)-3-(5-bromopentyl)-3-methylcyclohexanone 3k (55.0 mg, 0.21 mmol,53%) as a colourless oil. Enantiomeric excess (79% ee) was determined byintegration of the diastereomeric mixture of the corresponding(+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopic analysis. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 3.40 (t, J=6.7 Hz, 2 H), 2.28 (t, J=6.7 Hz, 2 H),2.14-2.21 (m, 1 H), 2.06-2.13 (m, 1 H), 1.80-1.92 (m, 4 H), 1.58-1.69(m, 1 H), 1.49-1.58 (m, 1 H), 1.41 (br. s., 2 H), 1.19-1.32 (m, 4 H),0.92 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.3, 53.7, 41.3,41.0, 38.6, 35.8, 33.8, 32.7, 28.8, 25.0, 22.6, 22.1. HRMS (ESI) m/zcalcd for C₁₂H₂₁BrNaO [M+Na]⁺: 283.0668, found: 283.0665. [α]²⁰₅₈₉=−2.06 (c 0.65, CHCl₃). IR (ATR) v (cm⁻¹): 729, 1227, 1461, 1709,2934.

Example 16 (−)-(R)-3-(4-(Benzyloxy)butyl)-3-methylcyclohexanone (3l)

CuCl (1.8 mg, 0.02 mmol, 0.10 eq) and ligand C (10.8 mg, 0.02 mmol, 0.10eq) were dissolved in ^(t)BuOMe (1.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (103 mg, 0.40 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 4-benzyloxy-1-butene (81 mg,0.50 mmol, 2.50 eq) in CH₂Cl₂ (0.20 mL) under an argon atmosphere. After40 min the solution became clear and yellow. AgNTf₂ (8.5 mg, 0.022 mmol,0.11 eq) was then added to the Cu-ligand mixture and it was stirred for10 min and filtered via syringe over 1 min to the hydrozirconationflask. The resulting dark mixture was allowed to stir for an additional10 min before 3-methyl-2-cyclohexenone (23 μL, 0.20 mmol, 1.0 eq) wasadded dropwise via syringe. Stirring at room temperature was continuedfor 12 h before the reaction was quenched by the addition of Et₂O (ca 3mL) and then NH₄Cl (1 M aq., ca 1.5 mL). The mixture was partitionedbetween water and Et₂O and the aqueous phase extracted with Et₂O (3×10mL). The combined organic phase was washed with NaHCO₃ (aq. sat., ca 10mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(−)-(R)-3-(4-(benzyloxy)butyl)-3-methyl-cyclohexanone 3l (29 mg, 0.11mmol, 53%) as a colourless oil. HPLC analysis indicated an enantiomericexcess of 90% [Chiralpak® IC; flow: 1.0 mL/min; hexane/i-PrOH: 95:5;λ=210 nm; major enantiomer (−)-(R)-3-(4-(benzyloxy)butyl)-3-methyl-cyclohexanone, t_(R)=21.20 min; minor enantiomer(+)-(S)-3-(4-(benzyloxy)-butyl)-3-methyl-cyclohexanone, t_(R)=25.60min]. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.38-7.14 (m, 5H), 4.42 (s, 2H),3.39 (t, J=6.4 Hz, 2H), 2.19 (d, J=7.5 Hz, 1H), 2.10 (d, J=13.5 Hz, 1H),2.03 (d, J=13.6 Hz, 1H), 1.85-1.70 (m, 2H), 1.62-1.39 (m, 4H), 1.34-1.13(m, 4H), 0.84 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.5, 138.7,128.5 (2C), 127.8 (2C), 127.6, 73.0, 70.3, 53.9, 41.6, 41.1, 38.7, 35.9,30.5, 25.1, 22.3, 20.2. HRMS (ESI) m/z calcd for C₁₈H₂₆NaC₂ [M+Na]⁺:297.1825, found: 297.1832. IR (ATR) v (cm⁻¹): 1103, 1455, 1712, 2853,2936. [α]²⁰ ₅₈₉=−2.76 (c 1.27, CHCl₃).

Example 17(+)-(R)-3-(4-((tert-Butyldimethylsilyl)oxy)butyl)-3-methylcyclohexanone(3m)

CuCl (1.8 mg, 0.02 mmol, 0.10 eq) and ligand C (10.8 mg, 0.02 mmol, 0.10eq) were dissolved in ^(t)BuOMe (1.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (103 mg, 0.40 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of4-[(tert-butyldimethylsilyl)oxy]-1-butene (93 mg, 0.50 mmol, 2.5 eq) inCH₂Cl₂ (0.20 mL) under an argon atmosphere. After 20 min the solutionbecame clear and yellow. AgNTf₂ (8.5 mg, 0.022 mmol, 0.11 eq) was thenadded to the Cu-ligand mixture and it was stirred for 15 min andfiltered via syringe over 1 min to the hydrozirconation reaction flask.The resulting dark mixture was allowed to stir for an additional 10 minbefore 3-methyl-2-cyclohexenone (23 μL, 0.20 mmol, 1.0 eq) was addeddropwise via syringe. Stirring at room temperature was continued 12 hbefore the reaction was quenched by the addition of Et₂O (ca 3 mL) andthen NH₄Cl (1 M aq., ca 1.5 mL). The mixture was partitioned betweenwater and Et₂O and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 10 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(+)-(R)-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-3-methylcyclohexanone3m (44 mg, 0.15 mmol, 75%) as a colourless oil. Enantiomeric excess (92%ee) was determined by integration of the diastereomeric mixture of thecorresponding (+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopicanalysis. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 3.61 (t, J=6.4 Hz, 2H), 2.27(t, J=6.8 Hz, 2H), 2.21-2.06 (m, 2H), 1.91-1.80 (m, 2H), 1.66-1.60 (m,1H), 1.57-1.44 (m, 3H), 1.33-1.22 (m, 4H), 0.91 (s, 3H), 0.89 (s, 9H),0.04 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.6, 63.1, 54.0,41.6, 41.2, 38.8, 35.9, 33.6, 26.1 (3C), 25.1, 22.3, 19.8, 18.5, −5.1(2C). HRMS (ESI) m/z calcd for C₁₇H₃₄NaC₂Si [M+Na]⁺: 321.2220, found:321.2219. IR (ATR) v (cm⁻¹): 1463, 1715, 2857, 2934. [α]²⁰ ₅₈₉=+0.23 (c1.27, CHCl₃).

Example 18(−)-(R)-3-(4-((tert-Butyldiphenylsilyl)oxy)butyl)-3-methylcyclohexanone(3n)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.04 mmol, 0.10eq) were dissolved in ^(t)BuOMe (2.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of4-(tert-butyldiphenylsilyl)oxy)-1-butene (310 mg, 1.00 mmol, 2.50 eq) inCH₂Cl₂ (0.20 mL) under an argon atmosphere. After 40 min the solutionbecame clear and yellow. AgNTf₂ (17.0 mg, 0.044 mmol, 0.11 eq) was thenadded to the Cu-ligand mixture and it was stirred for 10 min andfiltered via syringe over 1 min to the hydrozirconation flask. Theresulting dark mixture was allowed to stir for an additional 10 minbefore 3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0 eq) was addeddropwise via syringe. Stirring at room temperature was continued for 12h before the reaction was quenched by the addition of Et₂O (ca 6 mL) andthen NH₄Cl (1 M aq., ca 3 mL). The mixture was partitioned between waterand Et₂O and the aqueous phase extracted with Et₂O (3×15 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 15 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(−)-(R)-3-(4-((tert-butyldiphenylsilyl)oxy)butyl)-3-methylcyclohexanone3n (51 mg, 0.24 mmol, 61%) as a colourless oil. HPLC analysis indicatedan enantiomeric excess of 90% [Chiralpak® AY-H; flow: 0.7 mL/min;hexane/i-PrOH: 99:1; λ=210 nm; major enantiomer(−)-(R)-3-(4-((tert-butyldiphenylsilyl)oxy)butyl)-3-methyl-cyclohexanone,t_(R)=10.32 min; minor enantiomer(+)-(S)-3-(4-((tert-butyldiphenylsilyl)oxy)butyl)-3-methylcyclohexanone,t_(R)=11.08 min]. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.65-7.51 (m, 4H),7.41-7.23 (m, 6H), 3.59 (t, J=6.3 Hz, 2H), 2.18 (d, J=6.1 Hz, 2H), 2.08(d, J=13.5 Hz, 1H), 2.01 (dt, J=13.5, 1.3 Hz, 1H), 1.81-1.72 (m, 2H),1.57-1.47 (m, 1H), 1.47-1.38 (m, 3H), 1.29-1.10 (m, 4H), 0.97 (s, 9H),0.82 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.5, 135.7 (4C),134.2 (2C), 129.7 (2C), 127.7 (4C), 63.8, 54.0, 41.6, 41.2, 38.7, 35.8,33.3, 27.0 (3C), 25.1, 22.3, 19.7, 19.2. HRMS (ESI) m/z calcd forC₂₇H₃₈NaC₂Si [M+Na]⁺: 445.2533, found: 445.2518. IR (ATR) v (cm⁻¹):1110, 1472, 1713, 2857, 2932. [α]²⁰ ₅₈₉=−0.84 (c 1.45, CHCl₃).

Example 19(−)-(R)-3-(4-((tert-Butyldimethylsilyl)oxy)-4-methylpentyl)-3-methylcyclo-hexanone(3o)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.040 mmol,0.10 eq) were dissolved in t-BuOMe (2.0 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (23.2 mg, 0.060mmol, 0.15 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (206.0 mg, 0.80 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 4-tert-butyldimethylsililoxy-4-methyl-1-pentene (214 mg, 1.0 mmol, 2.5 eq) inCH₂Cl₂ (0.40 mL) under an argon atmosphere. After stirring for 15 min,the stirred solution containing the copper and ligand was transferredand filtered using a syringe filter to the clear yellow solution. Theresulting black mixture was allowed to stir for an additional 10 minbefore 3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0 eq) was addeddropwise via syringe. Stirring continued 12 h before the reaction wasquenched by the addition of Et₂O (ca 3 mL) and then NH₄Cl (1M aq., ca1.5 mL). The mixture was partitioned between the aqueous and Et₂O layersand the aqueous phase extracted with Et₂O (3×10 mL). The combinedorganic phase was washed with NaHCO₃ (aq. sat., ca 10 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(−)-(R)-3-(4-((tert-butyldimethylsilyl)oxy)-4-methylpentyl)-3-methylcyclohexanone3o (108 mg, 0.33 mmol, 83%) as a colourless oil. Enantiomeric excess(89% ee) was determined by integration of the diastereomeric mixture ofthe corresponding (+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopicanalysis. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 2.25 (t, J=7.2 Hz, 2H), 2.16(d, 1H, J=13.6 Hz), 2.08 (d, 1H, J=13.6 Hz), 1.87-1.80 (m, 2H),1.65-1.58 (m, 1H), 1.55-1.48 (m, 1H), 1.32-1.29 (m, 4H), 1.23-1.18 (m,2H), 1.15 (s, 6H), 0.90 (s, 3H), 0.82 (s, 9H), 0.03 (s, 6H). ¹³C NMR(100 MHz, CDCl₃) δ_(C)/ppm 212.7, 73.6, 54.2, 45.8, 42.5, 41.3, 38.9,36.0, 30.2, 29.9, 26.0 (3C), 25.2, 22.4, 18.3, 18.2, −1.90 (2C). MS(ESI) m/z calcd for C₁₉H₃₈NaC₂Si [M+Na]⁺: 349.2533, found: 349.2533. IR(ATR) v (cm⁻¹): 1462, 1714, 2855, 2954. [α]²⁰ ₅₈₉=−0.78 (c 1.56, CHCl₃).

Example 20 (+)-(S)-3-Methyl-3-(3-(trimethylsilyl)propyl)cyclohexanone(3p)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.04 mmol, 0.10eq) were dissolved in ^(t)BuOMe (2.0 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 1-trimethylsilyl-1-propene(80 μL, 0.50 mmol, 2.50 eq) in CH₂Cl₂ (0.40 mL) under an argonatmosphere. After 40 min the solution became clear and yellow. AgNTf₂(17.0 mg, 0.044 mmol, 0.11 eq) was then added to the Cu-ligand mixtureand it was stirred for 10 min and filtered via syringe over 1 min to thehydrozirconation reaction flask. The resulting dark mixture was allowedto stir for an additional 10 min before 3-methyl-2-cyclohexenone (45 μL,0.40 mmol, 1.0 eq) was added dropwise via syringe. Stirring at roomtemperature was continued for 12 h before the reaction was quenched bythe addition of Et₂O (ca 6 mL) and then NH₄Cl (1 M aq., ca 3 mL). Themixture was partitioned between water and Et₂O and the aqueous phaseextracted with Et₂O (3×15 mL). The combined organic phase was washedwith NaHCO₃ (aq. sat., ca 15 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Flash column chromatography of the yellow residue(1:9 EtOAc/petrol; SiO₂) gave(+)-(S)-3-methyl-3-(3-(trimethylsilyl)propyl)cyclohexanone 3p (37 mg,0.33 mmol, 82%) as a colourless oil. Enantiomeric excess (97% ee) wasdetermined by integration of the diastereomeric mixture of thecorresponding (+)-(R,R)-DPEN derivative by ¹³C NMR spectroscopicanalysis. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 2.27 (t, J=6.9 Hz, 2H), 2.18(d, J=13.4 Hz, 1H), 2.09 (d, J=13.5 Hz, 1H), 1.91-1.79 (m, 2H),1.68-1.58 (m, 1H), 1.58-1.47 (m, 1H), 1.34-1.18 (m, 4H), 0.90 (s, 3H),0.50-0.39 (m, 2H), −0.03 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm212.6, 54.0, 46.2, 41.2, 39.0, 36.0, 25.1, 22.3, 17.8, 17.5, −1.4 (3C).HRMS (ESI) m/z calcd for C₁₃H₂₆NaOSi [M+Na]⁺: 249.1645, found: 249.1645.IR (ATR) v (cm⁻¹): 1247, 1458, 1714, 2926, 2928. [α]²⁰ ₅₈₉=+0.21 (c1.43, CHCl₃).

Example 21(+)-(3R)-3-(4-((tert-Butyldimethylsilyl)oxy)-4-(4-chlorophenyl)butyl)-3-methylcyclohexanone(3q)

CuCl (3.6 mg, 0.04 mmol, 0.10 eq) and ligand C (21.6 mg, 0.040 mmol,0.10 eq) were dissolved in t-BuOMe (2.0 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (23.2 mg, 0.060mmol, 0.15 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (206 mg, 0.80 mmol, 2.0 eq) was added toa stirred, room temperature, solution oftert-butyl((1-(4-chlorophenyl)but-3-en-1-yl)oxy)dimethylsilane (0.30 mL,1.0 mmol, 2.5 eq) in CH₂Cl₂ (0.40 mL) under an argon atmosphere. Thestirred solution containing the copper and ligand was transferred andfiltered using a syringe filter to the clear yellow hydrozirconationsolution. The resulting black mixture was allowed to stir for anadditional 10 min before 3-methyl-2-cyclohexenone (45 μL, 0.40 mmol, 1.0eq) was added dropwise via syringe. Stirring continued 12 h before thereaction was quenched by the addition of Et₂O (ca 3 mL) and then NH₄Cl(1 M aq., ca 1.5 mL). The mixture was partitioned between the aqueousand Et₂O layers and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was washed with NaHCO₃ (aq. sat., ca 10 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂)(+)-(3R)-3-(4-((tert-Butyldimethylsilyl)oxy)-4-(4-chlorophenyl)butyl)-3-methylcyclohexanone3q (133.9 mg, 0.32 mmol, 82%) as a colourless oil. HPLC analysis of thealcohol derivative indicated a ˜1:1 diastereomeric ratio and anenantiomeric excess of 89% [Chiralpak® IC; flow: 1.0 mL/min;hexane/i-PrOH: 88:12; λ=210 nm; major enantiomer(+)-(3R)-3-(4-((tert-Butyldimethylsilyl)oxy)-4-(4-chlorophenyl)butyl)-3-methylcyclohexanone,t_(R)=16.7 min & 20.9 min; minor enantiomer(−)-(3S)-3-(4-((tert-Butyldimethylsilyl)oxy)-4-(4-chlorophenyl)-butyl)-3-methylcyclohexanone,t_(R)=19.5 min & 22.5 min]. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.22-7.27(m, 2 H), 7.15-7.21 (m, 2 H), 4.58 (ddd, J=7.4, 4.6, 2.7 Hz, 1 H),2.20-2.28 (m, 2 H), 2.03-2.16 (m, 2 H), 1.75-1.88 (m, 2 H), 1.44-1.67(m, 4 H), 1.12-1.37 (m, 4 H), 0.86 (s, 3 H), 0.86 (s, 9 H), 0.00 (s, 3H), −0.17 (d, J=1.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.2,144.2, 132.3, 128.2 (2 C), 127.1 (2 C), 74.2, 53.7, 41.7, 41.4, 41.0,38.6, 35.8, 25.8 (3C), 24.8, 22.1, 19.4, 18.1, −4.6, −5.0. HRMS (ESI)m/z calcd for C₂₃H₃₇ClNaC₂Si [M+Na]⁺: 431.2144 found: 431.2144. [α]²⁰₅₈₉=+0.51 (c 1.22, CHCl₃). IR (ATR) v (cm⁻¹): 776, 836, 1088, 1252,1713, 2857, 2932.

Example 22 (−)-(R)-3-Methyl-3-(4-phenylbutyl)cyclopentanone (4)

CuCl (1.8 mg, 0.02 mmol, 0.10 eq) and ligand C (18.8 mg, 0.020 mmol,0.10 eq) were dissolved in t-BuOMe (1.0 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (8.5 mg, 0.022mmol, 0.11 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (309.0 mg, 1.60 mmol, 3.0 eq) was addedto a stirred, room temperature, solution of hex-4-en-1-ylbenzene (0.3mL, 2.0 mmol, 5.0 eq) in CH₂Cl₂ (0.80 mL) under an argon atmosphere.After stirring for 15 min, the stirred solution containing the copperand ligand was transferred and filtered using a syringe filter to theclear yellow solution. The resulting black mixture was cooled with anice bath allowed to stir for an additional 20 min before3-methyl-2-cyclopentanone (20 μL, 0.20 mmol, 1.0 eq) was added dropwisevia syringe. Stirring continued 12 h leaving the ice melts so thereaction mixture slowly warmed up. The reaction was quenched by theaddition of Et₂O (ca 3 mL) and then NH₄Cl (1M aq., ca 1.5 mL). Themixture was partitioned between the aqueous and Et₂O layers and theaqueous phase extracted with Et₂O (3×10 mL). The combined organic phasewas washed with NaHCO₃ (aq. sat., ca 10 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. Flash column chromatography of the yellowresidue (1:9 EtOAc/petrol; SiO₂) gave(−)-(R)-3-Methyl-3-(4-phenylbutyl)cyclopentanone 4 (25.8 mg, 0.11 mmol,56%) as a colourless oil. HPLC analysis indicated an enantiomeric excessof 65% [Chiralpak® AY-H; flow: 1 mL/min; hexane/i-PrOH: 95:5; λ=210 nm;major enantiomer (+)-(R)-3-methyl-3-(4-phenylhexyl)cyclopentanone,t_(R)=9.50 min; minor enantiomer(−)-(S)-3-methyl-3-(4-phenylhexyl)cyclopentanone, t_(R)=8.60 min]. ¹HNMR (500 MHz, CDCl₃) δ_(H)/ppm 7.25-7.33 (m, 2 H), 7.13-7.22 (m, 3 H),2.64 (t, J=7.6 Hz, 2 H), 2.26-2.32 (m, 2 H), 2.05-2.12 (m, 1 H),1.98-2.05 (m, 1 H), 1.73-1.85 (m, 2 H), 1.64 (dt, J=15.1, 7.4 Hz, 2 H),1.26-1.47 (m, 4 H), 1.05 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃) δ_(C)/ppm24.4, 25.0, 32.1, 35.2, 35.8, 36.8, 39.5, 41.6, 52.2, 125.7, 128.28 (2C), 128.32 (2 C), 142.5, 220.2. HRMS (ESI) m/z calcd for C₁₆H₂₂NaO[M+Na]⁺: 253.1563 found: 253.1562. [α]²⁰ ₅₈₉=+22.64 (c 0.53, CHCl₃). IR(ATR) v (cm⁻¹): 699, 1454, 1496, 1711, 2930.

Example 23 (+)-(R)-3-Ethyl-3-(4-phenylbutyl)cyclohexanone (5)

CuCl (1.8 mg, 0.02 mmol, 0.10 eq) and ligand C (10.8 mg, 0.02 mmol, 0.10eq) were dissolved in ^(t)BuOMe (1 mL) and stirred at room temperaturefor 1 h. In another flask Cp₂ZrHCl (103 mg, 0.40 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 4-phenyl-1-butene (75 μL,0.50 mmol, 2.50 eq) in CH₂Cl₂ (0.20 mL) under an argon atmosphere. After40 min the solution became clear and yellow. AgNTf₂ (8.5 mg, 0.022 mmol,0.11 eq) was then added to the Cu-ligand mixture and it was stirred for10 min and filtered via syringe over 1 min to the hydrozirconationreaction flask. The resulting dark mixture was allowed to stir for anadditional 10 min before 3-ethyl-2-cyclohexenone (22 μL, 0.17 mmol, 0.85eq) was added dropwise via syringe. Stirring at room temperature wascontinued for 12 h before the reaction was quenched by the addition ofEt₂O (ca 3 mL) and then NH₄Cl (1 M aq., ca 1.5 mL). The mixture waspartitioned between water and Et₂O and the aqueous phase extracted withEt₂O (3×10 mL). The combined organic phase was washed with NaHCO₃ (aq.sat., ca 10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Flash column chromatography of the yellow residue (1:9 EtOAc/petrol;SiO₂) gave (+)-(R)-3-ethyl-3-(4-phenylbutyl)cyclohexanone 5 (25 mg, 0.09mmol, 58%) as a colourless oil. HPLC indicated an enantiomeric excess of92% [Chiralpak® ID; flow: 1 mL/min; hexane/i-PrOH: 99:1; λ=210 nm; majorenantiomer (+)-(R)-3-ethyl-3-(4-phenylbutyl)cyclohexanone, t_(R)=9.72min; minor enantiomer (−)-(S)-3-ethyl-3-(4-phenylbutyl)cyclohexanone,t_(R)=9.44 min]. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.24-7.35 (m, 2 H),7.12-7.23 (m, 3 H), 2.62 (t, J=7.8 Hz, 2 H), 2.28 (t, J=6.7 Hz, 2 H),2.13-2.21 (m, 2 H), 1.78-1.89 (m, 1 H), 1.49-1.67 (m, 4 H), 1.16-1.37(m, 6 H), 0.76 (t, J=7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm212.9, 142.8, 128.6 (3C), 125.9 (2C), 52.1, 41.3, 41.1, 36.6, 36.1,33.6, 32.3, 29.7, 22.7, 21.9, 7.6. HRMS (ESI) m/z calcd for C₁₈H₂₆NaO[M+Na]⁺: 281.1876, found: 281.1875. [α]²⁰ ₅₈₉=+2.40 (c 0.50, CHCl₃). IR(ATR) v (cm⁻¹): 1496, 1604, 1713, 2925, 3025.

Example 24 (+)-(R)-3,3,5-Trimethyl-5-(4-phenylbutyl)cyclohexanone (6)

CuCl (3.1 mg, 0.030 mmol, 0.10 eq) and ligand C (17.3 mg, 0.030 mmol,0.10 eq) were dissolved in t-BuOMe (1.5 mL) under an argon atmosphereand allowed to stir for 1 h at room temperature. AgNTf₂ (13.4 mg, 0.035mmol, 0.11 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (161.9 mg, 0.63 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 4-phenyl-1-butene (0.12 mL,0.78 mmol, 2.5 eq) in CH₂Cl₂ (0.40 mL) under an argon atmosphere. Afterstirring for 1 min, the stirred solution containing the copper andligand was transferred and filtered using a syringe filter to the clearyellow solution. The resulting black mixture was allowed to stir for anadditional 10 min before isophorone (47 μL, 0.31 mmol, 1.0 eq) and TMSCl(0.19 mL, 1.5 mmol) was added dropwise via syringe. Stirring continued12 h before the reaction was quenched by the addition of Et₂O (ca 3 mL)and then NH₄Cl (1M aq., ca 1.5 mL). The mixture was partitioned betweenthe aqueous and Et₂O layers and the aqueous phase extracted with Et₂O(3×10 mL). The combined organic phase was washed with NaHCO₃ (aq. sat.,ca 10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Flashcolumn chromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂)gave (+)-(R)-3,3,5-trimethyl-5-(4-phenylbutyl)cyclohexanone 6 (29 mg,0.11 mmol, 34%) as a yellow oil. HPLC analysis indicated an enantiomericexcess of 73% [Chiralpak® AY-H; flow: 1 mL/min; hexane/i-PrOH: 95:5;λ=210 nm; major enantiomer(+)-(R)-3,3,5-trimethyl-5-(4-phenylbutyl)cyclohexanone, t_(R)=6.8 min;minor enantiomer (−)-(S)-3,3,5-trimethyl-5-(4-phenylbutyl)cyclohexanone,t_(R)=8.0 min]. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.17-7.26 (m, 2 H),7.06-7.14 (m, 3 H), 2.54 (t, J=7.6 Hz, 2 H), 2.07-2.16 (m, 3 H), 2.05(m, J=0.7 Hz, 1 H), 1.39-1.59 (m, 4 H), 1.14-1.35 (m, 4 H), 0.96 (s, 6H), 0.92 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 212.6, 142.5,128.3 (2 C), 128.3 (2C), 125.7, 54.3, 53.1, 49.0, 44.6, 38.8, 36.1,35.9, 32.2, 32.1, 30.6, 27.4, 23.0. HRMS (ESI) m/z calcd for C₁₉H₂₈NaO[M+Na]⁺: 295.2032, found: 295.2025. [α]²⁰ ₅₈₉=+4.30 (c 1.15, CHCl₃). IR(ATR) v (cm⁻¹): 699, 747, 903, 1279, 1496, 1667, 1712, 2951.

Example 25 (−)-(R)-3-Hexyl-3-methylcycloheptanone (7a)

CuCl (3.1 mg, 0.030 mmol, 0.10 eq) and ligand C (17.3 mg, 0.030 mmol,0.10 eq) were dissolved t-BuOMe (1.5 mL) under an argon atmosphere andallowed to stir for 1 h at room temperature. AgNTf₂ (13.4 mg, 0.035mmol, 0.11 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (161.9 mg, 0.63 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 1-hexene (0.10 mL, 0.78mmol, 2.5 eq) in CH₂Cl₂ (0.31 mL) under an argon atmosphere. Afterstirring for 15 min, the stirred solution containing the copper andligand was transferred and filtered using a syringe filter to the clearyellow solution. The resulting black mixture was allowed to stir for anadditional 10 min before 3-methyl-2-cycloheptenone (41 μL, 0.31 mmol,1.0 eq) was added dropwise via syringe. Stirring continued 12 h beforethe reaction was quenched by the addition of Et₂O (ca 3 mL) and thenNH₄Cl (1 M aq., ca 1.5 mL). The mixture was partitioned between theaqueous and Et₂O layers and the aqueous phase extracted with Et₂O (3×10mL). The combined organic phase was washed with NaHCO₃ (aq. sat., ca 10mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:19 EtOAc/petrol; SiO₂) gave(−)-(R)-3-Hexyl-3-methylcycloheptanone 7a (45 mg, 0.21 mmol, 70%) as acolourless oil.

Enantiomeric excess (90% ee) was determined by HPLC analysis of thecorresponding enone. The enone was obtained as follows: a flaskcontaining Pd(TFA)₂ (18.9 mg, 0.057 mmol, 1 eq) and the ketone 7a (12mg, 0.057 mmol, 1 eq) was flashed with oxygen (balloon, 1 atm). DMSO (8μL, 0.11 mmol, 2 eq) and toluene (0.5 mL) were added and the suspensionwas warmed at 80° C. for 12 hours. After cooling down, the mixture wasconcentrated in vacuo and purified by flash column chromatography (1:19EtOAc/petrol; SiO₂) to give the desired enone that was directly analysedby HPLC. HPLC analysis indicated an enantiomeric excess of 90%[Chiralpak® IC; flow: 1 mL/min; hexane/i-PrOH: 95:5; λ=225 nm; majorenantiomer (−)-(R)-3-Methyl-3-(4-phenylhexyl)cyclohexanone t_(R)=20.2min; minor enantiomer (+)-(S)-3-Methyl-3-(4-phenylhexyl)cyclohexanone,t_(R)=21.4 min]. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 2.45 (d, J=12.0 Hz, 1H), 2.26-2.38 (m, 3 H), 1.64-1.77 (m, 2 H), 1.49-1.63 (m, 3 H),1.37-1.47 (m, 1 H), 1.08-1.29 (m, 10 H), 0.78-0.86 (m, 6 H). ¹³C NMR(100 MHz, CDCl₃) δ_(C)/ppm 214.3, 54.8, 43.9, 42.5 (2 C), 35.2, 31.8,30.0, 26.0, 24.7, 24.2, 23.4, 22.6, 14.1. HRMS (ESI) m/z calcd forC₁₄H₂₆NaO [M+Na]⁺: 233.1876 found: 233.1876. [α]²⁰ ₅₈₉=−0.60 (c 0.95,CHCl₃). IR (ATR) v (cm⁻¹): 699, 1229, 1368, 1455, 1730, 2929.

Example 26 (+)-(R)-3-Methyl-3-(4-phenylbutyl)cycloheptanone (7b)

CuCl (3.1 mg, 0.030 mmol, 0.10 eq) and ligand C (17.3 mg, 0.030 mmol,0.10 eq) were dissolved in CH₂Cl₂ (1.5 mL) under an argon atmosphere andallowed to stir for 1 h at room temperature. AgNTf₂ (13.4 mg, 0.035mmol, 0.11 eq) was added and the suspension was stirred for another 15min. In another flask, Cp₂ZrHCl (161.9 mg, 0.63 mmol, 2.0 eq) was addedto a stirred, room temperature, solution of 4-phenyl-1-butene (0.12 mL,0.78 mmol, 2.5 eq) in CH₂Cl₂ (0.31 mL) under an argon atmosphere. Afterstirring for 15 min, the stirred solution containing the copper andligand was transferred and filtered using a syringe filter to the clearyellow solution. The resulting black mixture was allowed to stir for anadditional 10 min before 3-methyl-2-cycloheptenone (41 μL, 0.31 mmol,1.0 eq) was added dropwise via syringe. Stirring continued 12 h beforethe reaction was quenched by the addition of Et₂O (ca 3 mL) and thenNH₄Cl (1M aq., ca 1.5 mL). The mixture was partitioned between theaqueous and Et₂O layers and the aqueous phase extracted with Et₂O (3×10mL). The combined organic phase was washed with NaHCO₃ (aq. sat., ca 10mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Flash columnchromatography of the yellow residue (1:9 EtOAc/petrol; SiO₂) gave(+)-(R)-3-methyl-3-(4-phenylbutyl)cycloheptanone 7b (41 mg, 0.16 mmol,51%) as a colourless oil. HPLC indicated an enantiomeric excess of 82%[Chiralpak® IC; flow: 1 mL/min; hexane/i-PrOH: 95:5; λ=210 nm; majorenantiomer (+)-(R)-3-methyl-3-(4-phenylbutyl)cycloheptanone, t_(R)=10.7min; minor enantiomer (−)-(S)-3-methyl-3-(4-phenylbutyl)cycloheptanone,t_(R)=11.7 min]. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.16-7.26 (m, 2 H),7.04-7.13 (m, 3 H), 2.54 (t, J=7.6 Hz, 2 H), 2.45 (d, J=12.0 Hz, 1 H),2.25-2.36 (m, 3 H), 1.64-1.75 (m, 2 H), 1.37-1.63 (m, 6 H), 1.10-1.34(m, 4 H), 0.81 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 214.2,142.6, 128.3 (2 C), 128.2 (2 C), 125.6, 54.7, 43.9, 42.6, 42.4, 35.9,35.2, 32.1, 25.9, 24.6, 24.1, 23.1. HRMS (ESI) m/z calcd for C₁₈H₂₆NaO[M+Na]⁺: 281.1876, found: 281.1876. [α]²⁰ ₅₈₉=+4.83 (c 0.63, CHCl₃). IR(ATR) v (cm⁻¹): 699, 1454, 1713, 2360, 3026.

Example 27 (R)-4a-methyl-3,4,4a,5,6,7-hexahydronaphthalen-1(2H)-one (8)

(S)-3-(4-hydroxybutyl)-3-methylcyclohexanone

To a stirred solution of(+)-(R)-3-(4-((tert-Butyldimethylsilyl)oxy)butyl)-3-methylcyclohexanone3m (110 mg, 0.37 mmol, 1.0 eq) in THF (3.7 mL) a 1M aqueous solution ofHCl was added and the resulting mixture was stirred at room temperaturefor 3 h. The mixture was then poured into 5 mL of saturated NaHCO₃solution. The aqueous layer was then extracted with Et₂O (3×3 mL) andthe combined organic extracts were washed with brine, dried over MgSO₄,filtered and evaporated. The crude product was purified by flash columnchromatography (Petrol:EtOAc, 7:3) to afford 57 mg of the unprotectedalcohol (84%).

(S)-4-(1-methyl-3-oxocyclohexyl)butanal

The above prepared alcohol (33 mg, 0.18 mmol,1.0 eq) was dissolved inCH₂Cl₂ (1.8 mL) and NaHCO₃ (151 mg, 0.21 mmol, 10 eq) was then added andthe mixture was cooled to 0° C. and Dess-Martin periodinane (91 mg, 1.80mmol, 1.20 eq) was added in one portion and the solution was allowed toreach room temperature. After 1 h a saturated solution of Na₂S₂O₃ (5 mL)was added. The aqueous phase was extracted with CH₂Cl₂ (3×2 mL). Thecombined organic extracts were washed with water, dried over MgSO₄,filtered and concentrated. A filtration through a silica pad providedthe desired aldehyde that was used in the next step without furtherpurification.

(R)-4a-methyl-3,4,4a,5,6,7-hexahydronaphthalen-1(2H)-one

HCl (0.1 mL) was added to a stirring solution of the aldehyde (20 mg,0.11 mmol) in THF (1.2 mL). The reaction was stirred overnight and thenit was neutralised with NaHCO₃ at 0° C. It was then diluted with Et₂Oand the organic phase was washed with water and brine. Flash columnchromatography (Petrol:EtOAc, 7:3) afforded the desired product (R)-8 in83% yield (15 mg, 0.09 mmol). The spectroscopic data was identical atthat reported in d′Augustin et al (Chem. Eur. J., 2007, 13, 9647-9662)for the opposite enantiomer. [α]²⁰ ₅₅₉=+78.2 (c 0.50, CHCl₃).

Examples 28-61 General Procedures

Synthesis of Phosphoramidite Ligands

According to a modified procedure from Trost et al (J. Am. Chem. Soc.,2011, 133 (48), 19483-19497), triethylamine (5.0 eq.) is added dropwiseto a stirred ice-cooled solution of PCl₃ (1.0 eq.) in CH₂Cl₂ (7 mL×mmolamine). The ice bath is removed and the solution left to warm to roomtemperature before amine (1.0 eq.) is added to the stirring solution.After 5 additional hours of stirring, binaphthol (1.0 eq.) is added tothe suspension and the subsequent mixture is left to stir for anadditional 18 h. The solution is then filtered on a small pad of silicaand Celite® and rinsed with CH₂Cl₂ (˜20 mL). The resulting solution isconcentrated under reduced pressure to afford a yellow residue. Afterflash column chromatography, the ligand is obtained as a crystallinesolid.

Synthesis of Alkyl Amines

According to a modified procedure from Davies et al (supra), thecorresponding ketone (2.0 eq.) is added to a stirring solution ofprimary amine (1.0 eq) in THF (˜0.2 M) at room temperature. After 5 min,NaB(OAc)₃H (1.5 eq.) is added into the reaction mixture at roomtemperature and the resulting suspension is stirred for 18-48 h. Et₂O(15 mL) and NaHCO₃ (aq. sat., ca 10 mL) are added to the suspension andstirring is continued for 30 min. The mixture is partitioned between theaqueous and Et₂O layers and the aqueous phase extracted with Et₂O (3×10mL). The combined organic phase is dried (MgSO₄), filtered andconcentrated under reduced pressure to afford the desired title amine.

In the case of recrystallization, the crude residue is then suspended inEt₂O, HCl (37% aq. solution) is added (2-5 drops) until a white solidprecipitated. The precipitate is isolated by filtration and washed withEtOAc and then recrystallized to give the HCl salt of the desiredsecondary amine. The crystals are added to a stirring biphasic mixturecontaining CH₂Cl₂ and a saturated NaOH solution. After stirring for 15minutes the phases are separated and the aqueous phase is extracted withCH₂Cl₂ (3×10 mL), dried (Na₂SO₄), filtered and concentred in vacuo toafford the desired secondary amine. The amine is used without furtherpurification or recrystallization.

In some cases, the above reaction can be followed immediately by thecreation of the corresponding ligand.

Synthesis of Aryl Amines

According to a modified procedure from Hampton et al (Chemmedchem, 2011,6(10)), TiCl₄ (1.1 eq, 1 M solution in DCM) is added slowly to anice-bathed solution of aryl-ketone (1.0 eq) in DCM (0.2 M solution). Thesolution is stirred for 10 minutes at room temperature and then asolution of amine (2.2 eq) in THF (2 M solution) is added dropwise tothe reaction mixture. The reaction flask is stirred for 3 hours. Asolution of NaB(CN)H₃ (1.2 eq) in THF (1 M solution) is added slowly tothe reaction mixture. MeOH (⅓ volume of DCM of first solution) is addedslowly to the reaction mixture. The reaction mixture is stirred at roomtemperature for 18 hours. NaOH (2M aq solution) is added slowly and thereaction mixture is stirred for 30 min. The reaction mixture is filteredon Celite® and washed with EtOAc. NaHCO₃ (aq. sat.) are added to thesuspension. The mixture is partitioned between the aqueous and organiclayers and the aqueous phase extracted with EtOAc (3 times). Thecombined organic phase is dried over MgSO₄, filtered and concentrated invacuo to give an oil. Purification by flash column chromatography (SiO₂)gave the desired amine.

Example 28 N-isopropyl-9H-fluoren-9-amine

Acetone (1.50 mL, 5.5 mmol, 2.0 eq.) was added to a stirring solution of9H-fluoren-9-amine (500 mg, 2.76 mmol, 1.0 eq.) in THF (10 mL) at roomtemperature. After 5 min, NaB(OAc)₃H (0.87 g, 2.84 mmol, 1.5 eq.) wasadded into the reaction mixture at room temperature and the resultingsuspension was stirred for 48 h. Et₂O (20 mL) and NaHCO3 (aq. sat., ca20 mL) were added to the suspension and stirring was continued for 30min. The mixture was partitioned between the aqueous and Et₂O layers andthe aqueous phase extracted with Et₂O (3×20 mL). The combined organicphase was dried (MgSO₄), filtered and concentrated under reducedpressure to afford the desired title product as a colourless oil (0.535g, 2.39 mmol, 87%). The amine was used without further purification. ¹HNMR (400 MHz, CDCl₃) b 7.67-7.81 (m, 4 H), 7.33-7.49 (m, 4 H), 4.96 (s,1 H), 3.30 (dt, J=12.2, 6.1 Hz, 1 H), 2.07 (br. s., 1 H), 1.18 (d, J=6.4Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃) b ppm 159.6, 147.5, 129.2, 118.7,112.0, 111.8, 55.0, 54.9, 45.4, 24.6, 23.8, 21.9. HRMS (ESI) m/z calcdfor C₁₆H₁₈N [M]⁺: 224.1434, found: 224.1443. IR (v_(max)/cm⁻¹) 2961,1600, 1256, 1047, 749.

Example 29 N-benzhydrylcyclohexanamine

Cyclohexanone (0.63 mL, 6.11 mmol, 1.1 eq) was added to a stirredsolution of diphenylmethanamine (1.20 mL, 6.42 mmol, 1.0 eq) in THF (20mL) at room temperature. After 5 minutes, NaB(OAc)₃H (1.94 g, 9.21 mmol,1.5 eq) was added in one portion. The resulting suspension was stirredfor about 48 hours, before Et₂O (10 mL) and NaHCO₃ (aq. sat., ca 10 mL)were added to the suspension and stirring was continued for 15additional minutes. The mixture was partitioned between the aqueous andEt₂O layers and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was concentrated in vacuo (˜5 mL). Then HCl (aq2.0 M, 1 mL) was added dropwise. The mixture was partitioned between theaqueous and Et₂O layers and the organic phase extracted with HCl (aq 2.0M, 3×10 mL). Then CH₂Cl₂ (20 mL) was added to the combined aqueousphases and NaOH (saturated with brine aq solution, 25%) was added untilthe mixture became basic (pH paper, pH˜14). The mixture was partitionedbetween the aqueous and CH₂Cl₂ layers and the aqueous phase extractedwith CH₂Cl₂ (3×10 mL). The combined organic phase was dried (MgSO₄),filtered and concentrated in vacuo to afford the desiredN-benzhydrylcyclohexanamine (1.01 g, 3.76 mmol, 61%). The amine was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.39 (d,J=7.1 Hz, 4H), 7.25-7.33 (m, 4 H), 7.15-7.23 (m, 2 H), 5.05 (s, 1 H),2.35-2.52 (m, 1 H), 1.96 (br. d, J=11.6 Hz, 2 H), 1.65-1.78 (m, 2 H),1.57 (br. s., 1 H), 1.35 (br. s, 1 H), 1.03-1.26 (m, 5 H). ¹³C NMR (100MHz, CDCl₃) δ_(C)/ppm 144.8 (2 C), 128.3 (4C), 127.3 (4C), 126.7 (2 C),63.6, 53.9, 33.9 (2 C), 26.2, 24.3-25.6 (2 C). MS (ESI) m/z [M+H]⁺:266.2 (100). IR (v_(max)/cm⁻¹): 3025, 2925, 2890, 1739, 1492, 1368,1229, 700.

Example 30 N-benzhydrylcyclopentanamine

Cyclopentanone (0.63 mL, 7.13 mmol, 1.1 eq) was added to a stirredsolution of diphenylmethanamine (1.20 mL, 6.42 mmol, 1.0 eq) in THF (20mL) at room temperature. After 5 minutes, NaB(OAc)₃H (2.13 g, 10.7 mmol,1.5 eq) was added in one portion. The resulting suspension was stirredfor about 48 hours, before Et₂O (10 mL) and NaHCO₃ (aq. sat., ca 10 mL)were added to the suspension and stirring was continued for 15additional minutes. The mixture was partitioned between the aqueous andEt₂O layers and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was concentrated in vacuo (˜5 mL). Then HCl (aq2.0 M, 1 mL) was added dropwise. The mixture was partitioned between theaqueous and Et₂O layers and the organic phase extracted with HCl (aq 2.0M, 3×10 mL). Then CH₂Cl₂ (20 mL) was added to the combined aqueousphases and NaOH (saturated with brine aq solution, 25%) was added untilthe mixture became basic (pH paper, pH˜14). The mixture was partitionedbetween the aqueous and CH₂Cl₂ layers and the aqueous phase extractedwith CH₂Cl₂ (3×15 mL). The combined organic phase was dried (MgSO₄),filtered and concentrated in vacuo to afford the desiredN-benzhydrylcyclopentanamine (1.30 g, 5.17 mmol, 76%). The amine wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm7.41-7.51 (m, 4 H), 7.35 (apparent td, J=7.6, 1.7 Hz, 4 H), 7.21-7.30(m, 2 H), 2.96-3.15 (m, 1 H), 1.83-2.00 (m, 2 H), 1.72 (br. s., 2 H),1.48-1.63 (m, 3 H), 1.35-1.46 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃)δ_(C)/ppm 144.5 (2 C), 128.4 (4 C), 127.2-127.6 (m, 4C), 126.5-127.0 (m,2 C), 65.6, 57.6, 33.2 (2 C), 23.8 (2 C). MS (ESI) m/z [M+H]⁺: 252.2(100). IR (v_(max)/cm⁻¹): 2970, 1739, 1449, 1367, 1229, 700.

Example 31 N-benzhydrylcyclooctanamine

Cycloctanone (0.7363 mL, 5.54 mmol, 1.1 eq) was added to a stirredsolution of diphenylmethanamine (0.86 mL, 4.9 mmol, 1.0 eq) in THF (20mL) at room temperature. After 5 minutes, NaB(OAc)₃H (1.764 g, 8.3 mmol,1.5 eq) was added in one portion. The resulting suspension was stirredfor about 48 hours, before Et₂O (10 mL) and NaHCO₃ (aq. sat., ca 10 mL)were added to the suspension and stirring was continued for 15additional minutes. The mixture was partitioned between the aqueous andEt₂O layers and the aqueous phase extracted with Et₂O (3×10 mL). Thecombined organic phase was concentrated in vacuo (˜5 mL). Then HCl (aq2.0 M, 1 mL) was added dropwise. The mixture was partitioned between theaqueous and Et₂O layers and the organic phase extracted with HCl (aq 2.0M, 3×10 mL). Then CH₂Cl₂ (20 mL) was added to the combined aqueousphases and NaOH (saturated with brine aq solution, 25%) was added untilthe mixture became basic (pH paper, pH˜14). The mixture was partitionedbetween the aqueous and CH₂Cl₂ layers and the aqueous phase extractedwith CH₂Cl₂ (3×10 mL). The combined organic phase was dried (MgSO₄),filtered and concentrated in vacuo to afford the desiredN-benzhydrylcyclooctanamine (0.98 g, 3.34 mmol, 60%). The amine was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm7.57-7.78 (m, 4 H), 7.45-7.55 (m, 4 H), 7.33-7.44 (m, 2 H), 5.21 (s, 1H), 2.89 (br. s., 1 H), 2.04 (s, 2 H), 1.93 (br. s., 2 H), 1.51-1.85 (m,11 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 144.5 (2 C), 128.1 (4 C),127.2 (4 C), 126.6 (2 C), 63.8, 54.2, 31.8 (2 C), 27.4 (2C), 25.4, 23.1.HRMS (ESI) m/z calcd for C₂₁H₂₈N [M]⁺: 294.2209, found: 294.2216. IR(v_(max)/cm⁻¹): 1738, 1492, 1368, 751.

Example 32 N-(bis(3,5-bis(trifluoromethyl)phenyl)methyl)propan-2-amine

TiCl₄ (6.1 mL, 6.1 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution ofbis(3,5-bis(trifluoromethyl)phenyl)methanone (2.5 g, 5.5 mmol, 1.0 eq)in DCM (30 mL). The solution was stirred for 5 minutes at roomtemperature and a solution of isopropylamine (1.0 mL, 12.1 mmol, 2.2 eq)in THF (6 ml, 2 M solution) was added dropwise to the reaction mixture.The reaction flask was stirred for 3 hours. A solution of NaB(CN)H₃(0.415 g, 6.61 mmol, 1.2 eq) in THF (7 mL, 1 M solution) was addedslowly to the reaction mixture. MeOH (10 mL) was added slowly to thereaction mixture. The reaction mixture was stirred at room temperaturefor 18 hours. NaOH (˜20 mL, 2M aq solution) was added slowly and thereaction mixture was stirred for 30 min. The reaction mixture wasfiltered on Celite® and washed with EtOAc (˜30 mL). The mixture waspartitioned between the aqueous and organic layers and the aqueous phaseextracted with EtOAc (3×10 mL). The combined organic phase was dried(MgSO₄), filtered and concentrated in vacuo to afford a yellow oil.Flash column chromatography of the residue (Petrol: CH₂Cl₂: Et₂O;89:10:1; SiO₂) gave the desiredN-(bis(3,5-bis(trifluoromethyl)phenyl)methyl)-propan-2-amine (0.73 g,1.46 mmol, 27%). ¹H NMR (300 MHz, CDCl₃) δ_(H)/ppm 7.88 (s, 4 H), 7.80(s, 2 H), 5.21 (s, 1 H), 2.70 (spt, J=6.2 Hz, 1 H), 1.27 (br. s., 1 H),1.14 (d, J=6.2 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 145.5 (2 C),131.0-133.2 (m, 2 C), 127.3-127.4 (m, 2 C), 127.3 (2 C), 124.5 (2 C),121.8 (s, 2 C), 63.4, 46.6, 23.1 (2 C). ¹⁹F NMR (380 MHz, CDCl₃)δ_(F)/ppm −62.85 (s, 12F). HRMS (ESI) m/z calcd for C₂₀H₁₆F₁₂N [M+H]⁺:498.1085, found: 498.1086. IR (v_(max)/cm⁻¹): 1371, 1276, 1168, 1126,898, 712.

Example 33 N-(bis(3-(trifluoromethyl)phenyl)methyl)propan-2-amine

TiCl₄ (3.5 mL, 3.50 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of bis(3-(trifluoromethyl)phenyl)methanone(1.0 g, 4.00 mmol, 1.0 eq) in DCM (17 mL). The solution was stirred for15 minutes at room temperature and a solution of isopropylamine (0.59mL, 6.90 mmol, 2.2 eq) in THF (3 ml, ˜1.5 M solution) was added dropwiseto the reaction mixture. The reaction flask was stirred for 3 hours. Asolution of NaB(CN)H₃ (0.237 g, 3.77 mmol, 1.2 eq) in THF (4 mL, 1 Msolution) was added slowly to the reaction mixture. MeOH (5.7 mL) wasadded slowly to the reaction mixture. The reaction mixture was stirredat room temperature for 18 hours. NaOH (˜10 mL, 2M aq solution) wasadded slowly and the reaction mixture was stirred for 30 min. Thereaction mixture was filtered on Celite® and washed with EtOAc (˜10 mL).NaHCO₃ (aq. sat., ca 10 mL) were added to the suspension. The mixturewas partitioned between the aqueous and organic layers and the aqueousphase extracted with EtOAc (3×10 mL). The combined organic phase wasconcentrated in vacuo. Et₂O (˜10 mL) was added to the oil. HCl (aq 2.0M, ˜2 mL) was added dropwise for about 1 min. HBr (1 mL, aq, 55%solution) was added dropwise and the mixture was left for 1 hour. Themixture was partitioned between the aqueous and Et₂O layers and theorganic phase extracted with HCl (aq 2.0 M, 15 mL). Then CH₂Cl₂ (10 mL)was added to the combined aqueous phases and NaOH (aq saturated withbrine solution, 25%) was added until the mixture became basic (pH paper,pH˜14). The mixture was partitioned between the aqueous and CH₂Cl₂layers and the aqueous phase extracted with CH₂Cl₂ (3×10 mL). Thecombined organic phase was dried (MgSO₄), filtered and concentrated invacuo to afford the desiredN-(bis(3-(trifluoromethyl)phenyl)methyl)propan-2-amine (0.545 g, 1.5mmol, 48%). The amine was used without further purification. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 7.69 (s, 2 H), 7.58 (d, J=7.6 Hz, 2 H), 7.48-7.53(m, 2 H), 7.40-7.47 (m, 2 H), 5.09 (s, 1 H), 2.72 (spt, J=6.3 Hz, 1 H),1.27 (br. s., 1 H), 1.11 (d, J=6.3 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃)δ_(C)/ppm 144.8 (br. s., 2 C), 131.1 (2 C), 130.7 (2 C), 129.1 (4 C),124.2 (q, J=4.0 Hz, 1 C), 124.0 (q, J=4.0 Hz, 1 C), 63.8, 46.3, 23.1 (2C). ¹⁹F NMR (380 MHz, CDCl₃) δ_(F)/ppm −62.51 (s, 6 F). HRMS (ESI) m/zcalcd for C₁₆H₁₀F₁₀N [M+H]⁺: 406.0648, found: 406.0639. IR(v_(max)/cm⁻¹): 2966, 1449, 1325, 1163, 1120, 707.

Example 34 N-(di-p-tolylmethyl)propan-2-amine

TiCl₄ (4.4 mL, 4.4 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of di-p-tolylmethanone (0.850 g, 4.0 mmol, 1.0eq) in DCM (22 mL). The solution was stirred for 5 minutes at roomtemperature and a solution of isopropylamine (0.76 mL, 8.90 mmol, 2.2eq) in THF (5 ml, ˜1.5 M solution) was added dropwise to the reactionmixture. The reaction flask was stirred for 3 hours. A solution ofNaB(CN)H₃ (0.305 g, 4.85 mmol, 1.2 eq) in THF (5 mL, 1 M solution) wasadded slowly to the reaction mixture. MeOH (7.5 mL) was added slowly tothe reaction mixture. The reaction mixture was stirred at roomtemperature for 18 hours. NaOH (˜10 mL, 2M aq solution) was added slowlyand the reaction mixture was stirred for 30 min. The reaction mixturewas filtered on Celite® and washed with EtOAc (˜10 mL). NaHCO₃ (aq.sat., ca 10 mL) were added to the suspension. The mixture waspartitioned between the aqueous and organic layers and the aqueous phaseextracted with EtOAc (3×10 mL). The combined organic phase wasconcentrated in vacuo. Et₂O (˜10 mL) was added to the oil. Then HCl (aq2.0 M, ˜2 mL) was added dropwise for about 1 min. The mixture waspartitioned between the aqueous and Et₂O layers and the organic phaseextracted with HCl (aq 2.0 M, 15 mL). Then CH₂Cl₂ (20 mL) was added tothe combined aqueous phases and NaOH (aq saturated with brine solution,25%) was added until the mixture became basic (pH paper, pH˜14). Themixture was partitioned between the aqueous and CH₂Cl₂ layers and theaqueous phase extracted with CH₂Cl₂ (3×10 mL). The combined organicphase was dried (MgSO₄), filtered and concentrated in vacuo to affordthe desired N-(di-p -tolylmethyl)propan-2-amine (0.622 g, 2.45 mmol,61%). The amine was used without further purification. ¹H NMR (400 MHz,CDCl₃) δ_(H)/ppm 7.24-7.30 (m, 4 H), 7.11 (d, J=8.1 Hz, 4 H), 4.92 (s, 1H), 2.75 (spt, J=6.3 Hz, 1 H), 2.32 (s, 6 H), 1.38 (br. s., 1 H), 1.09(d, J=6.3 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 141.8 (2 C),136.2 (2 C), 129.1 (4 C), 127.2 (4 C), 63.6, 46.0, 23.2 (2 C), 21.0 (2C). HRMS (ESI) m/z calcd for C₁₈H₂₄N [M+H]⁺: 254.1903, found: 254.1902.IR (v_(max)/cm⁻¹): 2960, 1510, 1460, 1167, 807, 768.

Example 35 N-(bis(4-methoxyphenyl)methyl)propan-2-amine

TiCl₄ (7.7 mL, 7.7 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of bis(4-methoxyphenyl)methanone (1.7 g, 7.0mmol, 1.0 eq) in DCM (38 mL). The solution was stirred for 10 minutes atroom temperature and a solution of isopropylamine (1.33 mL, 15.4 mmol,2.2 eq) in THF (15 ml, 1 M solution) was added dropwise to the reactionmixture. The reaction flask was stirred for 3 hours. A solution ofNaB(CN)H₃ (0.53 g, 8.4 mmol, 1.2 eq) in THF (8 mL, 1 M solution) wasadded slowly to the reaction mixture. MeOH (12 mL) was added slowly tothe reaction mixture. The reaction mixture was stirred at roomtemperature for 18 hours. NaOH (˜15 mL, 2M aq solution) was added slowlyand the reaction mixture was stirred for 30 min. The reaction mixturewas filtered on Celite® and washed with EtOAc (˜15 mL). NaHCO₃ (aq.sat., ca 15 mL) were added to the suspension. The mixture waspartitioned between the aqueous and organic layers and the aqueous phaseextracted with EtOAc (3×15 mL). The combined organic phase wasconcentrated in vacuo. Et₂O was added to the oil (˜8 mL). Then HCl (aq2.0 M, ˜3 mL) was added dropwise for about 5 min. The mixture waspartitioned between the aqueous and Et₂O layers and the organic phaseextracted with HCl (aq 2.0 M, 25 mL). Then CH₂Cl₂ (20 mL) was added tothe combined aqueous phases and NaOH (aq saturated with brine solution,25%) was added until the mixture became basic (pH paper, pH˜14). Themixture was partitioned between the aqueous and CH₂Cl₂ layers and theaqueous phase extracted with CH₂Cl₂ (3×15 mL). The combined organicphase was dried (MgSO₄), filtered and concentrated in vacuo to affordthe desired N-(bis(4-methoxyphenyl)methyl)propan-2-amine (0.94 g, 3.3mmol, 47%). The amine was used without further purification. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 7.24-7.33 (m, 4 H), 7.12 (d, J=7.8 Hz, 4 H), 4.94(s, 1 H), 2.77 (spt, J=6.2 Hz, 1 H), 2.33 (s, 6 H), 1.30 (br. s., 1 H),1.10 (d, J=6.4 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 141.8 (2 C),136.2 (2 C), 128.7-129.5 (m, 4 C), 127.2 (4 C), 63.6, 46.0, 23.2 (2 C),21.0 (2 C). HRMS (EI) m/z calcd for C₁₈H₂₃NO₂ [M+H]⁺: 285.1729, found:285.1729. IR (v_(max)/cm⁻¹): 2960, 1510, 1468, 1379, 1365, 1167, 1021,807, 768.

Example 36 N-(di(naphthalen-1-yl)methyl)cyclohexanamine

TiCl₄ (5.8 mL, 5.8 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of di(naphthalen-1-yl)methanone (1.5 g, 5.3mmol, 1.0 eq) in DCE (20 mL) in a sealed tube. The solution was stirredfor 10 minutes at room temperature and then a solution ofcyclohexylamine (1.7 mL, 11.7 mmol, 2.2 eq) in DCE (6 mL) was addeddropwise to the reaction mixture. The reaction flask was sealed andheated under reflux (80° C.) for 3 hours. Once cooled to roomtemperature, NaB(CN)H₃ (0.67 g, 10.6 mmol, 2.0 eq) and a solution ofisopropylamine (1.3 mL, 15.6 mmol, 2.2 eq) in DCE (10 mL) were addeddropwise sequentially to the reaction mixture. The reaction flask wassealed and heated under reflux (90° C.) for 15 hours. The reactionmixture was allowed to cool down to room temperature and then cooledwith an ice bath. NaOH (˜20 mL, 2M aq solution) was added slowly and thereaction mixture was stirred for 1 hour. The reaction mixture wasfiltered on Celite® and washed with DCM (˜20 mL). NaHCO₃ (aq. sat., ca15 mL) were added to the suspension. The mixture was partitioned betweenthe aqueous and organic layers and the aqueous phase extracted with DCM(3×15 mL). The combined organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give an oil. Purification by two flash columnchromatography (Toluene; SiO₂) and then (95:5 Petrol/EtOAc; SiO₂) of theresidue gave the desired amine (1.03 g, 2.81 mmol, 53%). ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 8.08-8.32 (m, 2 H), 7.87-7.96 (m, 2 H), 7.79 (d,J=8.1 Hz, 2 H), 7.55 (d, J=6.8 Hz, 2 H), 7.46-7.52 (m, 4 H), 7.43 (t,J=8.1 Hz, 2 H), 6.66 (s, 1 H), 2.65-2.83 (m, 1 H), 2.03-2.28 (m, 2 H),1.69-1.85 (m, 2 H), 1.50-1.66 (m, 3 H), 1.05-1.37 (m, 4 H). ¹³C NMR (100MHz, CDCl₃) δ_(C)/ppm 139.2 (1 C), 134.1 (2 C), 131.4 (2 C), 128.9 (3C), 127.6 (2 C), 126.2 (2 C), 125.6-125.8 (2 C), 125.5 (2 C), 125.4 (2C), 123.1 (2 C), 55.4 (1 C), 55.0 (1 C), 34.1 (2 C), 26.1 (1 C), 25.2 (2C). HRMS (ESI) m/z calcd for C₂₇H₂₈N [M+H]⁺: 366.2216, found: 366.2205.IR (v_(max)/cm⁻¹): 3457, 3016, 2970, 1738, 1375, 1228, 776.

Example 37 N-(di(naphthalen-1-yl)methyl)propan-2-amine

TiCl₄ (7.8 mL, 7.8 mmol, 1.0 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of di(naphthalen-1-yl)methanone (2.0 g, 7.1mmol, 1.0 eq) in DCE (20 mL) in a sealed tube. The solution was stirredfor 10 minutes at room temperature and then a solution of isopropylamine(1.3 mL, 15.6 mmol, 2.2 eq) in DCE (1.3 mL) was added dropwise to thereaction mixture. The reaction flask was sealed and heated under reflux(80° C.) for 4 hours. Once cooled to room temperature, NaB(CN)H₃ (0.53g, 8.5 mmol, 1.2 eq) and a solution of isopropylamine (1.3 mL, 15.6mmol, 2.2 eq) in DCE (1.3 mL) were added dropwise sequentially to thereaction mixture. The reaction flask was sealed and heated under reflux(90° C.) for 18 hours. The reaction mixture was allowed to cool down toroom temperature and then cooled with an ice bath. NaOH (˜40 mL, 2M aqsolution) was added slowly and the reaction mixture was stirred for 1hour. The reaction mixture was filtered on Celite® and washed with EtOAc(˜50 mL). NaHCO₃ (aq. sat., ca 35 mL) were added to the suspension. Themixture was partitioned between the aqueous and organic layers and theaqueous phase extracted with EtOAc (3×30 mL). The combined organic phasewas dried over MgSO₄, filtered and concentrated in vacuo to give an oil.Purification by two flash column chromatography (Toluene; SiO₂) and then(95:5; Petrol/EtOAc; SiO₂) of the residue gave the desired amine (0.364g, 1.12 mmol, 16%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm7.94-8.00 (m, 2 H), 7.85 (d, J=8.1 Hz, 2 H), 7.63 (d, J=6.8 Hz, 2 H),7.52-7.58 (m, 4 H), 7.46-7.52 (m, 2 H), 6.68 (s, 1 H), 3.22 (spt, J=6.3Hz, 1 H), 1.65 (s, 1 H), 1.31 (d, J=7.2 Hz, 6 H). ¹³C NMR (100 MHz,CDCl₃) δ_(C)/ppm 139.0 (1 C), 134.1 (1 C), 131.4 (1 C), 128.9 (2 C),127.6 (2 C), 126.3 (2 C), 125.5 (2 C), 125.4 (2 C), 55.6 (1 C), 47.4 (1C), 23.3 (2 C). HRMS (ESI) m/z calcd for C₂₄H₂₄N [M+H]⁺: 326.1888,found: 326.1903. IR (v_(max)/cm⁻¹):3457, 3016, 2970, 1738, 1375, 1228,776.

Example 38 N-(di(naphthalen-2-yl)methyl)propan-2-amine

TiCl₄ (10.3 mL, 10.3 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of di(naphthalen-2-yl)methanone (2.65 g, 9.38mmol, 1.0 eq) in DCM (50 mL). The solution was stirred for 10 minutes atroom temperature and then a solution of isopropylamine (1.8 mL, 20.6mmol, 2.2 eq) in THF (10 ml, 2 M solution) was added dropwise to thereaction mixture. The reaction flask was stirred for 3 hours. A solutionof NaB(CN)H₃ (0.71 g, 11.2 mmol, 1.2 eq) in THF (12 mL, 1 M solution)was added slowly to the reaction mixture. MeOH (17 mL) was added slowlyto the reaction mixture. The reaction mixture was stirred at roomtemperature for 18 hours. NaOH (˜25 mL, 2M aq solution) was added slowlyand the reaction mixture was stirred for 30 min. The reaction mixturewas filtered on Celite® and washed with EtOAc (˜20 mL). NaHCO₃ (aq.sat., ca 15 mL) were added to the suspension. The mixture waspartitioned between the aqueous and organic layers and the aqueous phaseextracted with EtOAc (3×20 mL). The combined organic phase was driedover MgSO₄, filtered and concentrated in vacuo to give an oil.Purification by flash column chromatography (93:7; Petrol/EtOAc; SiO₂)gave N-(di(naphthalen-2-yl)methyl)propan-2-amine (2.24 g, 6.9 mmol, 74%)as a colourless solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 8.15 (s, 2 H),8.03 (d, J=8.1 Hz, 2 H), 7.95 (d, J=8.4 Hz, 4 H), 7.74 (dd, J=8.4, 1.5Hz, 2 H), 7.56-7.67 (m, 4 H), 5.51 (s, 1 H), 3.06 (spt, J=6.2 Hz, 1 H),1.72 (br. s., 1 H), 1.36 (d, J=6.2 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃)δ_(C)/ppm 141.8 (2 C), 133.4 (2 C), 132.6 (2 C), 128.2 (2 C), 127.9 (2C), 127.6 (2 C), 126.0 (2 C), 125.9 (2 C), 125.7 (2 C), 125.6 (2 C),64.3 (1 C), 46.2 (1 C), 23.3 (2 C). HRMS (ESI) m/z calcd for C₃₂H₅₂N[M+H]⁺: 326.1888, found: 326.1903. IR (v_(max)/cm⁻¹): 3055, 2960, 1600,1362, 907, 757, 734.

Example 39 Di(naphthalen-2-yl)methanol

According to a modified procedure from Hsieh et al (Tetrahedron, 2009,65(16), 3062-3068), THF (˜30 mL) was added to immerse magnesium turnings(1.01 g, 41.6 mmol, 1.3 eq). The reaction was heated at 40° C. and I₂ (1crystal) was added to the solution. After 10 minutes, 2-bromonaphtalene(2.17 mL, 15.65 mmol, 1.05 eq) and THF (20 mL) were added slowly to thereaction mixture. The reaction mixture was refluxed for 3 hours. Uponcooling at room temperature, 2-naphthaldehyde (5.1 g, 32.0 mmol, 1.0 eq)was added dropwise (1 drop/second) to the reaction mixture and stirredfor 18 hours. H₂O (˜30 mL), HCl (˜20 mL, 2 M) and Et₂O (˜40 mL) wereadded to the reaction mixture, which was stirred at room temperature for20 minutes. The mixture was partitioned between the aqueous and organiclayers and the aqueous phase extracted with Et₂O (3×50 mL). The combinedorganic phase was dried over MgSO₄, filtered and concentrated in vacuoto give di(naphthalen-2-yl)methanol (9.0 g, 31.6 mmol, 99%) as acolourless solid. The molecule was used without further purification. ¹HNMR (400 MHz, CDCl₃) δ_(H)/ppm 7.95 (s, 2 H), 7.81-7.90 (m, 5 H), 7.80(s, 1 H), 7.48-7.55 (m, 5 H), 7.47 (d, J=1.7 Hz, 1 H), 6.15 (s, 1 H),2.59 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 140.9 (2 C), 133.2 (2C), 132.9 (2 C), 128.4 (2 C), 128.1 (2 C), 127.7 (2 C), 126.2 (2 C),126.0 (2 C), 125.2 (2 C), 124.9 (2 C), 76.4. HRMS (ESI) m/z calcd forC₂₁H₁₆NaO [M+Na]⁺: 307.1093, found: 307.1091. IR (v_(max)/cm⁻¹): 3450,2970, 1739, 1436, 1217, 897, 757.

Example 40 Di(naphthalen-2-yl)methanone

According to a modified procedure from Azuma et al (Tetrahedron, 2013,69(6), 1694-1699), MnO₂ (8.4 g, 96.7 mmol, 10 eq) was added to astirring solution of di(naphthalen-2-yl)methanol (2.75 g, 9.68 mmol, 1.0eq) in DCM (20 mL) at room temperature. The solution was stirred for 24hours. The reaction mixture was then filtered over Celite® andconcentrated in vacuo to give the desired di(naphthalen-2-yl)methanone(2.70 g, 9.56 mmol, 99%) as colourless solid. The molecule was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 8.34 (s,2 H), 8.00-8.03 (m, 4 H), 7.95 (apparent t, J=7.2 Hz, 4 H), 7.65(apparent td, J=7.6, 1.2 Hz, 2 H), 7.58 (apparent td, J=7.6, 1.2 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 196.8 (1 C), 135.3 (2 C), 135.2(2 C), 132.3 (2 C), 131.8 (2 C), 127.8 (4 C), 126.8 (4 C), 125.9 (4 C).MS (ESI) [M+Na]⁺: 305.1 (100). IR (v_(max)/cm⁻¹): 2915, 1653, 1379,1334, 1194, 763.

Example 41 Bis(3,5-dimethylphenyl)methanol

According to a modified procedure from Hsieh et al (supra), THF (˜10 mL)was added to immerse magnesium turnings (471 mg, 119.4 mmol, 1.3 eq).The reaction was heated at 40° C. and I₂ (1 crystal) was added to thesolution. After 10 minute, 1-bromo-3,5-dimethylbenzene (2.17 mL, 15.65mmol, 1.05 eq) and THF (5 mL) was added slowly to the reaction mixture.The reaction mixture was refluxed for 4 hours. Upon cooling at roomtemperature, 3,5-dimethylbenzaldehyde (2.0 g, 14.91 mmol) was addeddropwise (1 drop/second) to the reaction mixture and stirred for 18hours. H₂O (˜10 mL), HCl (˜5 mL, 2 M) and Et₂O (˜10 mL) were addedsuccessfully to the reaction mixture which was stirred at roomtemperature for 20 minutes. The mixture was partitioned between theaqueous and organic layers and the aqueous phase extracted with Et₂O(3×15 mL). The combined organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give bis(3,5-dimethylphenyl)methanol (3.7 g,15.35 mmol, 98%) as a colourless solid. The molecule was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.01 (s, 4 H),6.91 (s, 2 H), 5.71 (s, 1 H), 2.31 (s, 12 H), 1.59 (br. s., 1 H). ¹³CNMR (100 MHz, CDCl₃) δ_(C)/ppm 143.9 (2 C), 137.9 (2 C), 129.1 (2 C),124.2 (2 C), 76.3 (1 C), 21.3 (2 C). HRMS (ESI) m/z calcd for C₁₇H₂₀NaO[M+Na]⁺: 263.1406, found: 263.1408. IR (v_(max)/cm⁻¹): 2970, 1750, 1373,1215, 1056, 896, 750, 702.

Example 42 Bis(3,5-dimethylphenyl)methanone

According to a modified procedure from Azuma et al (supra), MnO₂ (8.0 g,92.3 mmol, 6 eq) was added to a stirring solution ofbis(3,5-dimethylphenyl)methanol (3.7 g, 15.3 mmol, 1.0 eq) in DCM (30mL) at room temperature. The solution was stirred for 18 hours. MnO₂(8.0 g, 92.3 mmol, 6 eq) was added to the reaction mixture and thereaction mixture was stirred for another 24 hours. The reaction mixturewas then filtered over Celite® and concentrated in vacuo to give thedesired bis(3,5-dimethylphenyl)methanone (3.5 g, 14.7 mmol, 96%) ascolourless solid. The molecule was used without further purification. ¹HNMR (400 MHz, CDCl₃) δ_(H)/ppm 7.39 (s, 4 H), 7.22 (s, 2 H), 2.38 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 197.6 (1 C), 138.0 (2 C), 137.8(4 C), 133.9 (2 C), 127.7 (4 C), 21.2 (4 C). HRMS (ESI) m/z calcd forC₁₇H₁₈NaO [M+Na]⁺: 261.1250, found: 261.1244. IR (v_(max)/cm⁻¹): 2915,1649, 1599, 1379, 1320, 1192, 763.

Example 43 N-(bis(3,5-di-tert-butylphenyl)methyl)propan-2-amine

TiCl₄ (6.9 mL, 6.90 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of bis(3,5-di-tert-butylphenyl)methanone (2.55g, 6.27 mmol, 1.0 eq) in DCM (35 mL). The solution was stirred for 10minutes at room temperature and then a solution of isopropylamine (1.2mL, 13.8 mmol, 2.2 eq) in THF (7 ml, 2 M solution) was added dropwise tothe reaction mixture. The reaction flask was stirred for 3 hours. Asolution of NaB(CN)H₃ (0.47 g, 7.5 mmol, 1.2 eq) in THF (7.5 mL, 1 Msolution) was added slowly to the reaction mixture. MeOH (11.4 mL) wasadded slowly to the reaction mixture. The reaction mixture was stirredat room temperature for 18 hours. NaOH (˜20 mL, 2M aq solution) wasadded slowly and the reaction mixture was stirred for 30 min. Thereaction mixture was filtered on Celite® and washed with DCM (˜20 mL).NaHCO₃ (aq. sat., ca 15 mL) were added to the suspension. The mixturewas partitioned between the aqueous and organic layers and the aqueousphase extracted with DCM (3×10 mL). The combined organic phase was driedover MgSO₄, filtered and concentrated in vacuo to give an oil. Petrol(˜25 mL) and Et2O (˜15 mL) were added to the crude mixture. ConcentratedHCl (˜5 mL, 37% w/v solution) was added. The mixture was left andcrystals formed after 1 hour. The reaction flask was then stored at −20°C. overnight. The reaction mixture was filtered and washed with coldpetrol. The crystals were collected and dried under high vacuum to givethe desired N-(bis(3,5-di-tert-butylphenyl)methyl)propan-2-amine (0.51g, 1.11 mmol, 18%). ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.31 (br. s., 4H), 7.29 (br. s., 2 H), 4.98 (br. s., 1 H), 2.68-2.86 (m, 1 H),1.37-1.40 (m, 1 H), 1.35 (br. s, 36 H), 1.14 (d, J=6.2 Hz, 6 H). ¹³C NMR(100 MHz, CDCl₃) δ_(C)/ppm 150.3 (4 C), 143.9 (2 C), 121.7 (4 C), 120.5(2 C), 65.7 (1 C), 46.2 (1 C), 34.8 (2 C), 31.5 (12 C), 23.3 (2 C). HRMS(ESI) m/z calcd for C₃₂H₅₂N [M+H]⁺: 450.4092, found: 450.4094. IR(v_(max)/cm⁻¹): 2960, 2867, 1598, 1477, 1393, 1248, 876, 728.

Example 44 N-(bis(3,5-dimethylphenyl)methyl)propan-2-amine

TiCl₄ (16.2 mL, 16.2 mmol, 1.1 eq, 1 M solution in DCM) was added slowlyto an ice-bathed solution of bis(3,5-dimethylphenyl)methanone (3.5 g,14.7 mmol, 1.0 eq) in DCM (80 mL). The solution was stirred for 10minutes at room temperature and then a solution of isopropylamine (2.8mL, 32.3 mmol, 2.2 eq) in THF (17 ml, 2 M solution) was added dropwiseto the reaction mixture. The reaction flask was stirred for 3 hours. Asolution of NaB(CN)H₃ (1.1 g, 17.6 mmol, 1.2 eq) in THF (18 mL, 1 Msolution) was added slowly to the reaction mixture. MeOH (26 mL) wasadded slowly to the reaction mixture. The reaction mixture was stirredat room temperature for 18 hours. NaOH (˜30 mL, 2M aq solution) wasadded slowly and the reaction mixture was stirred for 30 min. Thereaction mixture was filtered on Celite® and washed with EtOAc (˜20 mL).NaHCO₃ (aq. sat., ca 15 mL) were added to the suspension. The mixturewas partitioned between the aqueous and organic layers and the aqueousphase extracted with EtOAc (3×10 mL). The combined organic phase wasdried over MgSO₄, filtered and concentrated in vacuo to give an oil.Purification by flash column chromatography (19:1; Petrol/EtOAc; SiO₂)gave the desired amine (2.44 g, 8.6 mmol, 59%) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ_(H)/ppm 7.00 (s, 4 H), 6.85 (s, 2 H), 4.83 (s, 1 H),2.75 (dt, J=12.5, 6.3 Hz, 1 H), 2.30 (s, 12 H), 1.24-1.39 (m, 1 H), 1.10(d, J=6.3 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 144.6 (2 C),137.8 (4 C), 128.4 (2 C), 125.0 (4 C), 64.2 (1 C), 46.1 (1 C), 23.2 (2C), 21.4 (4 C). HRMS (ESI) m/z calcd for C₂₀H₂₈N [M+H]⁺: 282.2225,found: 282.2216. IR (v_(max)/cm⁻¹): 2956, 1598, 1469, 1375, 1166, 861,740.

Example 45 Bis(2-methoxyphenyl)methanol

According to a modified procedure from Diederich et al (J. Am. Chem.Soc., 1988, 110 (6), 1679-1690), THF (˜30 mL) was added to immersemagnesium turnings (1.1 g, 38.5 mmol, 1.05 eq). The reaction was heatedat 40° C. and I₂ (1 crystal) was added to the solution. After 10minutes, 1-bromo-2-methoxybenzene (4.8 mL, 47.7 mmol, 1.3 eq) and THF(15 mL) was added slowly to the reaction mixture. The reaction mixturewas refluxed for 4 hours. Upon cooling at room temperature,2-methoxybenzaldehyde (4.4 mL, 36.7 mmol, 1.0 eq) was added dropwise (1drop/second) to the reaction mixture and stirred for 18 hours. H₂O (˜40mL), HCl (˜25 mL, 2 M) and Et₂O (˜40 mL) were added successfully to thereaction mixture which was stirred at room temperature for 20 minutes.The mixture was partitioned between the aqueous and organic layers andthe aqueous phase extracted with Et₂O (3×50 mL). The combined organicphase was dried over MgSO₄, filtered and concentrated in vacuo to givebis(2-methoxyphenyl)methanol (8.5 g, 34.7 mmol, 94%) as a colourlesssolid. The molecule was used without further purification. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 7.27-7.31 (m, 2 H), 7.23-7.27 (m, 2 H), 6.95 (td,J=7.5, 0.9 Hz, 2 H), 6.91 (d, J=8.3 Hz, 2 H), 6.37 (d, J=5.4 Hz, 1 H),3.84 (s, 6 H), 3.57 (dd, J=5.1, 0.7 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃)δ_(C)/ppm 156.8 (2 C), 130.9 (2 C), 128.4 (2 C), 127.8 (2 C), 120.5 (2C), 110.4 (2 C), 67.4 (1 C), 55.4 (2 C). HRMS (ESI) m/z calcd forC₁₅H₁₆NaC₃ [M+Na]⁺: 267.0992, found: 267.0999. IR (v_(max)/cm⁻¹): 2970,1759, 1342, 1204.

Example 46 Bis(2-methoxyphenyl)methanone

According to a modified procedure from Diederich et al (supra), MnO₂(7.6 g, 88.0 mmol, 5 eq) was added to a stirring solution ofbis(2-methoxyphenyl)methanol (4.2 g, 17.4 mmol, 1.0 eq) in DCM (50 mL)at room temperature. The solution was stirred for 18 hours. MnO₂ (7.6 g,88.0 mmol, 5 eq) was added to the reaction mixture and the reactionmixture was stirred for another 24 hours. The reaction mixture was thenfiltered over Celite® and concentrated in vacuo to give the desiredbis(2-methoxyphenyl)methanone (3.3 g, 13.7 mmol, 79%) as a colourlesssolid. The molecule was used without further purification. ¹H NMR (400MHz, CDCl₃) δ_(H)/ppm 7.52 (dd, J=7.6, 1.7 Hz, 2 H), 7.44 (ddd, J=8.3,7.4, 2.0 Hz, 2 H), 6.99 (td, J=7.5, 0.7 Hz, 2 H), 6.92 (d, J=8.3 Hz, 2H), 3.67 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 195.3, 158.2 (2C), 132.5 (2 C), 130.3 (2 C), 130.2 (2 C), 120.3 (2 C), 111.4 (2 C),55.6 (2 C). HRMS (ESI) m/z calcd for C₁₅H₁₄NaO [M+Na]⁺: 265.0835, found:265.0836. IR (v_(max)/cm⁻¹): 2970, 1730, 1597, 1369, 1250, 1023, 751.

Example 47 N-(bis(2-methoxyphenyl)methyl)propan-2-amine

According to a modified procedure from Hampton et al (supra), TiCl₄(15.2 mL, 15.1 mmol, 1.1 eq, 1 M solution in DCM) was added slowly to anice-bathed solution of bis(2-methoxyphenyl)methanone (3.33 g, 13.8 mmol,1.0 eq) in DCM (40 mL). The solution was stirred for 10 minutes at roomtemperature and then a solution of isopropylamine (3.5 mL, 41.2 mmol,3.0 eq) in THF (20 ml, 2 M solution) was added dropwise to the reactionmixture. The reaction flask was stirred for 6 hours. A solution ofNaB(CN)H₃ (4.32 g, 68.7 mmol, 5.0 eq) in THF (68 mL, 1 M solution) wasadded slowly to the reaction mixture. MeOH (24 mL) was added slowly tothe reaction mixture. The reaction mixture was stirred at roomtemperature for 18 hours. NaOH (_(˜)50 mL, 2M aq solution) was addedslowly and the reaction mixture was stirred for 30 min. The reactionmixture was filtered on Celite® and washed with Et₂O (˜70 mL). NaHCO₃(aq. sat., ca 50 mL) were added to the suspension. The mixture waspartitioned between the aqueous and organic layers and the aqueous phaseextracted with Et₂O (3×50 mL). The combined organic phase was dried overMgSO₄, filtered and concentrated in vacuo to give an oil. Et₂O (˜50 mL)were added to the crude mixture. Concentrated HCl (˜5 mL, 37% w/vsolution) was added. The mixture was left and crystals formed after 5min.

The mixture was partitioned between the aqueous and Et₂O layers and theorganic phase extracted with HCl (aq 2.0 M, 3×30 mL). Then CH₂Cl₂ (20mL) was added to the combined aqueous phases and NaOH (aq saturated withbrine solution, 25%) was added until the mixture became basic (pH paper,pH˜14). The mixture was partitioned between the aqueous and CH₂Cl₂layers and the aqueous phase extracted with CH₂Cl₂ (3×50 mL). Thecombined organic phase was dried (MgSO₄), filtered and concentrated invacuo to afford the desired N-(bis(2-methoxyphenyl)methyl)propan-2-amine(2.14 g, 7.4 mmol, 54%). The amine was used without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.37 (d, J=7.3 Hz, 2 H), 7.20 (td,J=7.7, 1.5 Hz, 2 H), 6.93 (t, J=7.5 Hz, 2 H), 6.85 (d, J=8.3 Hz, 2 H),5.63 (s, 1 H), 3.80 (s, 6 H), 2.76 (spt, J=6.2 Hz, 1 H), 1.86-2.25 (m, 1H), 1.12 (d, J=6.1 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 157.2 (2C), 131.8 (2 C), 128.5 (2 C), 127.4 (2 C), 120.3 (2 C), 110.7 (2 C),55.4 (2 C), 52.5, 46.2, 23.1 (2 C). HRMS (ESI) m/z calcd forC₁₈H₂₄NO₂[M+H]⁺: 286.1802, found: 286.1804. IR (v_(max)/cm⁻¹): 2950,1771, 1709, 1598, 1380, 1351, 1229.

Example 48(R)—N-(bis(3,5-bis(trifluoromethyl)phenyl)methyl)-N-isopropyldi-naphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine

Triethylamine (1.23 mL, 8.81 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.14 mL, 1.61 mmol, 1.1 eq.) inCH₂Cl₂ (11 mL). The ice bath was removed and the solution left to warmto room temperature beforeN-(bis(3,5-bis(trifluoromethyl)phenyl)methyl)propan-2-amine (730 mg,1.47 mmol, 1.0 eq.) was added to the stirring solution. After 5additional hours of stirring, (R)-binaphthol (546 mg, 1.90 mmol, 1.3eq.) was added to the suspension and the subsequent mixture was left tostir for an additional 18 h. The solution was then filtered on a smallpad of silica and Celite® and rinsed with CH₂Cl₂ (˜20 mL). The resultingsolution was concentrated under reduced pressure to afford a yellowresidue. After flash columns chromatography (Petrol: CH₂Cl₂: Et₂O;4.3:0.3:0.3: SiO₂) and (Petrol: CH₂Cl₂: Toluene; 4.2:0.6:0.6: SiO₂), theligand was obtained as a crystalline white solid (452 mg, 0.56 mmol,38%). ¹H NMR (500 MHz, CD₂Cl₂) δ ppm 8.00 (d, J=8.8 Hz, 1 H), 7.96 (d,J=12.0 Hz, 1 H), 7.86-7.94 (m, 4 H), 7.74-7.84 (m, 3 H), 7.39-7.51 (m, 3H), 7.32-7.38 (m, 1 H), 7.11-7.30 (m, 5 H), 5.94 (d, J=15.8 Hz, 1 H),3.58 (dq, J=12.8, 6.4 Hz, 1 H), 1.19 (d, J=6.6 Hz, 3 H), 0.95 (d, J=6.6Hz, 3 H). ¹³C NMR (125 MHz, CD₂Cl₂) δ ppm 149.9 (d, J=7.4 Hz), 149.7,145.2 (d, J=4.6 Hz), 145.2, 133.2, 132.8, 132.7, 132.5, 132.4, 132.3,132.2, 131.4, 131.3, 130.4, 129.7 (2 C), 129.5 (2 C), 129.0, 128.9,128.7, 127.5, 127.3, 126.8, 126.8, 125.7, 125.4, 125.0 (d, J=4.6 Hz),124.2 (d, J=5.5 Hz), 122.7, 122.6, 121.8, 60.1 (d, J=23.0 Hz), 48.0,23.4 (2 C). ³¹P NMR (200 MHz, CD₂Cl₂) δ ppm 147.96 (s, 1P). ¹⁹F NMR (380MHz, CDCl₃) δ ppm −62.8 (s, 6 F), −62.9 (s, 6 F). HRMS (EI) m/z calcdfor C₄₀H₂₆F₁₂NO₂P [M−iPr]⁺: 811.1510, found: 811.1501. [α]²⁰ ₅₈₉=−130.93(c 1.08, CHCl₃). IR (v_(max)/cm⁻¹): 1372, 1279, 1174, 1136, 949, 822.

Example 49(R)—N-(bis(3,5-di-tert-butylphenyl)methyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine

Triethylamine (1.00 mL, 7.33 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.12 mL, 1.23 mmol, 1.0 eq.) inCH₂Cl₂ (9 mL). The ice bath was removed and the solution left to warm toroom temperature beforeN-(bis(3,5-di-tert-butylphenyl)methyl)propan-2-amine (553 mg, 1.23 mmol,1.0 eq.) was added to the stirring solution. After 5 additional hours ofstirring, (R)-binaphthol (458 mg, 1.23 mmol, 1.0 eq.) was added to thesuspension and the subsequent mixture was left to stir for an additional18 h. The solution was then filtered on a small pad of silica andCelite® and rinsed with CH₂Cl₂ (˜20 mL). The resulting solution wasconcentrated under reduced pressure to afford a yellow residue. Afterflash columns chromatography (Petrol: CH₂Cl₂: Et₃N; 79.5:20:0.5: SiO₂)and (Petrol: CH₂Cl₂: Et₃N; 85:15:0.03: SiO₂), the ligand was obtained asa crystalline white solid (472 mg, 0.61 mmol, 50%). ¹H NMR (500 MHz,CDCl₃) δ ppm 7.86-7.95 (m, 3 H), 7.82 (d, J=8.8 Hz, 1 H), 7.33-7.45 (m,8 H), 7.25-7.33 (m, 3 H), 7.19-7.24 (m, 1 H), 7.14 (d, J=0.9 Hz, 2 H),5.64 (d, J=18.9 Hz, 1 H), 3.54 (dq, J=9.8, 6.5 Hz, 1 H), 1.37 (s, 18 H),1.31-1.35 (m, 18 H), 1.00-1.08 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃) δ ppm150.8 (d, J=6.5 Hz), 150.5 (2 C), 150.2 (2 C), 150.1, 143.4, 142.7,132.8 (2 C), 132.7 (2 C), 131.3, 130.4, 130.1, 129.3, 128.2, 128.2,127.13, 127.11, 125.9, 125.8, 124.6, 124.2, 124.0 (d, J=5.5 Hz), 123.3(d, J=4.6 Hz), 123.2, 122.3, 122.3, 121.7, 120.2, 120.1, 61.5 (d, J=27.0Hz), 46.8, 35.0 (2 C), 34.9 (2 C), 31.6 (6 C), 31.5 (6C), 22.9, 22.9.³¹P NMR (200 MHz, CDCl₃) δ ppm 152.00 (s, 1P). HRMS (EI) m/z calcd forC₄₇H₃₈NO₂P [M-iPr]⁺: 720.3970, found: 720.4001. [α]²⁰ ₅₈₉=−80.83 (c1.09, CHCl₃). IR (v_(max)/cm⁻¹): 2964, 1739, 1593, 1463, 1367, 1231,750.

Example 50(R)—N-(bis(3,5-dimethylphenyl)methyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine

Triethylamine (2.50 mL, 17.79 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.31 mL, 3.55 mmol, 1.0 eq.) inCH₂Cl₂ (26 mL). The ice bath was removed and the solution left to warmto room temperature beforeN-(bis(3,5-dimethylphenyl)methyl)propan-2-amine (1.0 g, 3.55 mmol, 1.0eq.) was added to the stirring solution. After 5 additional hours ofstirring, (R)-binaphthol (1.02 g, 3.55 mmol, 1.0 eq.) was added to thesuspension and the subsequent mixture was left to stir for an additional18 h. The solution was then filtered on a small pad of silica andCelite® and rinsed with CH₂Cl₂ (˜30 mL). The resulting solution wasconcentrated under reduced pressure to afford a yellow residue. Afterflash column chromatography (Petrol: CH₂Cl₂: Et₃N; 79:20:1: SiO₂), theligand was obtained as a crystalline white solid (1.53 g, 2.57 mmol,73%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.98 (d, J=8.8 Hz, 1 H), 7.95 (t,J=7.4 Hz, 2 H), 7.89 (d, J=8.8 Hz, 1 H), 7.39-7.50 (m, 5 H), 7.30-7.37(m, 2 H), 7.24-7.30 (m, 1 H), 7.16 (s, 2 H), 7.01 (s, 3 H), 6.98 (s, 1H), 5.62 (d, J=18.3 Hz, 1 H), 3.64 (br. d, J=5.0 Hz, 1 H), 2.43 (s, 6H), 2.41 (s, 6 H), 1.11 (d, J=6.3 Hz, 3 H), 1.03 (d, J=6.3 Hz, 3 H). ¹³CNMR (125 MHz, CDCl₃) δ ppm 150.6 (d, J=7.4 Hz), 150.0, 143.7, 143.7,143.7, 137.6, 137.5, 132.8 (d, J=9.2 Hz), 131.3, 130.5, 130.2, 129.4,128.6 (3 C), 128.3, 128.2, 127.2, 127.1, 126.8, 126.8 (3 C), 126.8,125.9, 125.8, 124.7, 124.3, 124.1 (d, J=4.6 Hz), 122.5, 122.2, 121.8,60.6 (d, J=26.0 Hz), 46.7, 23.1, 22.9, 21.6 (4 C). ³¹P NMR (200 MHz,CDCl₃) δ ppm 151.05 (s, 1P). HRMS (EI) m/z calcd for C₄₀H₃₈NO₂P [M]⁺:595.2640, found: 595.2632. [α]²⁰ ₅₈₉=−122.04 (c 1.55, CHCl₃). IR(v_(max)/cm⁻¹): 2960, 2100, 11789, 1380, 1229, 1213.

Example 51(R)—N-cyclohexyl-N-(di(naphthalen-1-yl)methyl)dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine

Triethylamine (1.96 mL, 14.10 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.25 mL, 2.80 mmol, 1.0 eq.) inCH₂Cl₂ (20 mL). The ice bath was removed and the solution left to warmto room temperature before N-(di(naphthalen-1-yl)methyl)cyclohexanamine(1.03 g, 2.80 mmol, 1.0 eq.) was added to the stirring solution. After 5additional hours of stirring, (R)-binaphthol (806 mg, 2.80 mmol, 1.0eq.) was added to the suspension and the subsequent mixture was left tostir for an additional 18 h. The solution was then filtered on a smallpad of silica and Celite® and rinsed with CH₂Cl₂ (˜35 mL). The resultingsolution was concentrated under reduced pressure to afford a yellowresidue. After flash column chromatography (Petrol: CH₂Cl₂: Et₃N;79:20:1: SiO₂), the ligand was obtained as a crystalline white solid(415 mg, 0.61 mmol, 22%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.41 (br. s., 1H), 7.90-8.02 (m, 2 H), 7.72-7.89 (m, 7 H), 7.31-7.61 (m, 11 H),7.11-7.29 (m, 7 H), 3.23 (br. s., 1 H), 1.99 (br. s., 1 H), 1.10-1.77(m, 6 H), 0.74 (d, J=11.0 Hz, 1 H), 0.38-0.63 (m, 2 H). ¹³C NMR (125MHz, CDCl₃) δ ppm 150.6, 150.1, 134.6, 134.4, 133.2, 132.9, 131.7,131.4, 130.6, 130.5, 129.6, 129.4 (2 C), 129.2, 128.9 (2 C), 128.7 (2C), 128.6, 128.5 (2 C), 127.4 (2 C), 127.3, 126.6 (2 C), 126.3 (2 C),126.2, 126.04, 126.01 (2 C), 125.4, 125.4, 125.0, 124.7, 124.1, 123.8,122.7, 122.4, 57.5, 55.8, 26.8 (3 C), 25.6 (2 C). ³¹P NMR (200 MHz,CDCl₃) δ ppm 148.95 (s, 1P). HRMS (EI) m/z calcd for C₄₇H₃₈NO₂P [M]⁺:679.2640, found: 679.2650. [α]²⁰ ₅₈₉=−79.63 (c 1.05, CHCl₃). IR(v_(max)/cm⁻¹): 2930, 1730, 1420, 1350, 1213, 750.

Example 52(R)—N-(di(naphthalen-1-yl)methyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]-dioxaphosphepin-4-amine

Triethylamine (0.78 mL, 5.68 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.10 mL, 1.12 mmol, 1.0 eq.) inCH₂Cl₂ (8 mL). The ice bath was removed and the solution left to warm toroom temperature before N-(di(naphthalen-1-yl)methyl)propan-2-amine (365mg, 1.12 mmol, 1.0 eq.) was added to the stirring solution. After 5additional hours of stirring, (R)-binaphthol (321 mg, 1.12 mmol, 1.0eq.) was added to the suspension and the subsequent mixture was left tostir for an additional 15 h. The solution was then filtered on a smallpad of silica and Celite® and rinsed with CH₂Cl₂ (˜30 mL). The resultingsolution was concentrated under reduced pressure to afford a yellowresidue. After flash column chromatography (Petrol: CH₂Cl₂: Et₃N;77:12:1: SiO₂), the ligand was obtained as a crystalline white solid(283 mg, 0.44 mmol, 39%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.39 (br. s., 1H), 7.61-7.98 (m, 9 H), 7.31-7.59 (m, 10 H), 6.97-7.31 (m, 7 H), 3.81(d, J=5.7 Hz, 1 H), 1.10-1.37 (m, 3 H), 0.94 (br. s., 3 H). ¹³C NMR (125MHz, CDCl₃) δ ppm 150.7, 150.1, 138.9, 138.0, 134.6, 134.4, 133.2,133.0, 131.7, 131.4, 130.7, 130.6, 129.6, 129.4, 129.2, 129.1, 128.9,128.8, 128.6, 128.6, 127.5, 127.4, 126.7, 126.6, 126.3, 126.13, 126.09,126.0, 125.5 (4 C), 125.1, 124.6, 124.5 (d, J=5.5 Hz), 124.0, 123.8,122.7, 122.6, 121.9, 55.1 (d, J=26.0 Hz), 48.5, 24.6, 23.6. ³¹P NMR (200MHz, CDCl₃) δ ppm 148.61 (s, 1P). HRMS (EI) m/z calcd for C₄₄H₃₄NO₂P[M]⁺: 639.2327, found: 639.2354. [α]²⁰ ₅₈₉=−79.63 (c 1.05, CHCl₃). IR(v_(max)/cm⁻¹): 2970, 1739, 1368, 1229, 1216.

Example 53(R)—N-(di(naphthalen-2-yl)methyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]-dioxaphosphepin-4-amine

Triethylamine (1.87 mL, 13.4 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.23 mL, 2.68 mmol, 1.0 eq.) inCH₂Cl₂ (17 mL). The ice bath was removed and the solution left to warmto room temperature before N-(di(naphthalen-2-yl)methyl)propan-2-amine(782 mg, 2.68 mmol, 1.0 eq.) was added to the stirring solution. After 5additional hours of stirring, (R)-binaphthol (767 mg, 2.68 mmol, 1.0eq.) was added to the suspension and the subsequent mixture was left tostir for an additional 18 h. The solution was then filtered on a smallpad of silica and Celite® and rinsed with CH₂Cl₂ (˜30 mL). The resultingsolution was concentrated under reduced pressure to afford a yellowresidue. After flash column chromatography (Petrol: CH₂Cl₂: Et₃N;89:10:1→80:20:1 SiO₂), the ligand was obtained as a crystalline whitesolid (1230 mg, 1.92 mmol, 72%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.03 (s,1 H), 7.85-7.96 (m, 7 H), 7.71-7.79 (m, 2 H), 7.66 (br. dd, J=8.5, 1.6Hz, 2 H), 7.59 (s, 1 H), 7.52-7.57 (m, 2 H), 7.34-7.51 (m, 7 H),7.26-7.33 (m, 3 H), 7.19-7.24 (m, 1 H), 6.02 (d, J=17.7 Hz, 1 H),3.63-3.77 (m, 1 H), 1.15 (d, J=6.6 Hz, 3 H), 1.08 (d, J=6.6 Hz, 3 H).¹³C NMR (125 MHz, CDCl₃) δ ppm 150.8 (d, J=7.4 Hz), 150.2, 141.3, 141.2,133.8, 133.6, 133.2, 133.1, 133.0, 131.8, 130.9, 130.7, 129.9, 128.7,128.7 (2 C), 128.6 (3 C), 128.4, 128.14, 128.09 (d, J=3.7 Hz), 128.0,127.7 (d, J=3.7 Hz), 127.6, 127.6, 127.5, 126.6, 126.5, 126.4 (3 C),126.4, 126.3, 125.1, 124.8, 124.4 (d, J=5.5 Hz), 122.8, 122.6, 122.2,61.6, 47.5, 23.7, 23.6. ³¹P NMR (200 MHz, CDCl₃) δ ppm 150.18 (s, 1P).HRMS (EI) m/z calcd for C₄₄H₃₄NO₂P [M]⁺: 639.2327, found: 639.2354.[α]²⁰ ₅₈₉=−67.66 (c 0.99, CHCl₃). IR (v_(max)/cm⁻¹): 2970, 1739, 1367,1229, 1216, 946, 820, 751.

Example 54(S)—N-(bis(4-methoxyphenyl)methyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine

Triethylamine (1.15 mL, 8.28 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.14 mL, 1.66 mmol, 1.0 eq.) inCH₂Cl₂ (12 mL). The ice bath was removed and the solution left to warmto room temperature before N-(bis(4-methoxyphenyl)methyl)propan-2-amine(472 mg, 1.66 mmol, 1.0 eq.) was added to the stirring solution. After 5additional hours of stirring, (S)-binaphthol (474 mg, 1.66 mmol, 1.0eq.) was added to the suspension and the subsequent mixture was left tostir for an additional 18 h. The solution was then filtered on a smallpad of silica and Celite® and rinsed with CH₂Cl₂ (˜30 mL). The resultingsolution was concentrated under reduced pressure to afford a yellowresidue. After flash column chromatography (Petrol: CH₂Cl₂: Et₃N;80:19:1 SiO₂), the ligand was obtained as a crystalline white solid (438mg, 0.73 mmol, 44%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.92 (d, J=8.5 Hz, 1H), 7.89 (dd, J=7.9, 4.1 Hz, 2 H), 7.82 (d, J=8.8 Hz, 1 H), 7.33-7.46(m, 6 H), 7.25-7.31 (m, 3 H), 7.19-7.24 (m, 5 H), 7.14-7.19 (m, 2 H),5.65 (d, J=17.3 Hz, 1 H), 3.58 (td, J=6.6, 4.1 Hz, 1 H), 2.40 (s, 3 H),2.38 (s, 3 H), 1.08 (d, J=6.6 Hz, 3 H), 0.98 (d, J=6.6 Hz, 3 H). ¹³C NMR(125 MHz, CDCl₃) δ ppm 150.9 (d, J=6.5 Hz, 1 C), 150.4, 141.2 (d, J=5.5Hz), 141.1 (d, J=3.7 Hz), 137.0, 136.9, 133.2, 133.1, 131.7, 130.9,130.6, 129.8, 129.4 (2 C), 129.3 (2 C), 129.2 29.2, 129.2, 129.1, 128.7,128.6, 127.6, 127.5, 126.3, 126.2, 125.1, 124.7, 124.4 (d, J=5.5 Hz),122.9, 122.7, 122.1 (d, J=2.8 Hz), 60.5, 47.1, 23.6, 23.3, 21.6 (2 C).³¹P NMR (200 MHz, CDCl₃) δ ppm 150.85 (s, 1P). HRMS (EI) m/z calcd forC₃₈H₃₄NO₂P [M−1]⁺: 598.2147. found: 598.2151. [α]²⁰ ₅₈₉=+144.24 (c 0.99,CHCl₃). IR (v_(max)/cm⁻¹): 3016, 2970, 1730, 1436, 1369, 1229, 899, 732.

Example 55(R)—N-(di-p-tolylmethyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]-dioxaphos-phepin-4-amine

Triethylamine (1.60 mL, 11.61 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.20 mL, 2.32 mmol, 1.0 eq.) inCH₂Cl₂ (17 mL). The ice bath was removed and the solution left to warmto room temperature before N-(di-p-tolylmethyl)propan-2-amine (589 mg,2.32 mmol, 1.0 eq.) was added to the stirring solution. After 5additional hours of stirring, (R)-binaphthol (665 mg, 2.32 mmol, 1.0eq.) was added to the suspension and the subsequent mixture was left tostir for an additional 18 h. The solution was then filtered on a smallpad of silica and Celite® and rinsed with CH₂Cl₂ (˜30 mL). The resultingsolution was concentrated under reduced pressure to afford a yellowresidue. After flash column chromatography (Petrol: CH₂Cl₂: Et₃N;80:19:1 SiO₂), the ligand was obtained as a crystalline white solid (574mg, 1.04 mmol, 43%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.92 (d, J=8.8 Hz, 1H), 7.87-7.91 (m, 2 H), 7.82 (d, J=8.8 Hz, 1 H), 7.33-7.46 (m, 7 H),7.25-7.31 (m, 2H), 7.22 (d, J=7.3 Hz, 5 H), 7.15-7.19 (m, 2 H), 5.65 (d,J=17.7 Hz, 1 H), 3.58 (dq, J=11.0, 6.6 Hz, 1 H), 2.40 (s, 3 H), 2.38 (s,3 H), 1.08 (d, J=6.6 Hz, 3 H), 0.98 (d, J=6.6 Hz, 3 H). ¹³C NMR (125MHz, CDCl₃) δ ppm 150.5 (d, J=6.5 Hz), 149.9, 140.7 (d, J=6.5 Hz), 140.6(d, J=4.6 Hz), 136.55, 136.51, 132.73, 132.69, 131.3, 130.5, 130.1,129.3, 129.0 (2 C), 128.9 (2 C), 128.8, 128.7, 128.7, 128.7, 128.2,128.2, 127.1, 127.0, 125.9, 125.8, 124.6, 124.3, 124.0 (d, J=4.6 Hz),122.4, 122.2, 121.7, 60.3, 46.7, 23.1, 22.9, 21.13, 21.10. ³¹P NMR (200MHz, CDCl₃) δ ppm 150.84 (s, 1P). HRMS (EI) m/z calcd for C₃₈H₃₄NO₂P[M]⁺: 567.2327, found: 567.2348. [α]²⁰ ₅₈₉=−157.46 (c 1.00, CHCl₃). IR(v_(max)/cm⁻¹): 2974, 1510, 1232, 947, 820, 721.

Example 56(R)—N-(bis(3-(trifluoromethyl)phenyl)methyl)-N-isopropyldinaphtho-[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine

Triethylamine (1.00 mL, 7.72 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.13 mL, 3.11 mmol, 1.0 eq.) inCH₂Cl₂ (10 mL). The ice bath was removed and the solution left to warmto room temperature beforeN-(bis(3-(trifluoromethyl)phenyl)methyl)propan-2-amine (521 mg, 1.44mmol, 1.0 eq.) was added to the stirring solution. After 5 additionalhours of stirring, (R)-binaphthol (413 mg, 1.44 mmol, 1.0 eq.) was addedto the suspension and the subsequent mixture was left to stir for anadditional 18 h. The solution was then filtered on a small pad of silicaand Celite® and rinsed with CH₂Cl₂ (˜30 mL). The resulting solution wasconcentrated under reduced pressure to afford a yellow residue. Afterflash column chromatography (Petrol: CH₂Cl₂: Et₃N; 80:19:1 SiO₂), theligand was obtained as a crystalline white solid (652 mg, 0.96 mmol,67%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.95 (d, J=8.8 Hz, 1 H), 7.89 (t,J=7.6 Hz, 2 H), 7.82 (s, 1 H), 7.79 (d, J=8.8 Hz, 1 H), 7.73 (s, 1 H),7.61-7.66 (m, 1 H), 7.58 (d, J=7.6 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.46(t, J=7.6 Hz, 1 H), 7.38-7.44 (m, 4 H), 7.36 (d, J=7.6 Hz, 1 H),7.19-7.30 (m, 4 H), 5.80 (d, J=16.4 Hz, 1 H), 3.59 (sxt, J=6.2 Hz, 1 H),1.14 (d, J=6.6 Hz, 3 H), 0.97 (d, J=6.2 Hz, 3 H). ¹³C NMR (125 MHz,CDCl₃)δ ppm 149.8 (d, J=7.4 Hz), 149.4, 143.7, 132.7 (d, J=9.2 Hz),132.2, 131.9, 131.4, 131.1, 131.0, 130.8, 130.54, 130.1, 129.5, 129.0,128.8, 128.3 (d, J=8.3 Hz), 127.1, 127.0, 126.1, 126.0, 125.7 (t, J=4.2Hz), 125.5 (t, J=3.2 Hz), 125.2 (d, J=2.8 Hz), 124.8, 124.5, 124.3 (dd,J=7.4, 3.7 Hz, 2 C), 123.8 (d, J=5.5 Hz), 123.0 (d, J=2.8 Hz), 122.0,121.73, 121.69, 60.0 (d, J=23.0 Hz), 47.1, 23.2, 23.0 (d, J=4.6 Hz). ³¹PNMR (200 MHz, CDCl₃) δ ppm 149.00 (s, 1P). ¹⁹F NMR (380 MHz, CDCl₃) δppm −62.5 (s, 3 F), −62.6 (s, 3 F). HRMS (EI) m/z calcd for C₃₈H₂₈F₆NO₂P[M−1]⁺: 675.1762, found: 675.1758. [α]²⁰ ₅₈₉=−159.00 (c 1.01, CHCl₃). IR(v_(max)/cm⁻¹): 2975, 1591, 1329, 1231, 1165, 1125, 948, 828, 803, 751.

Example 57(S)—N-benzhydryl-N-cyclooctyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphe-pin-4-amine

Triethylamine (1.16 mL, 8.34 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.15 mL, 1.67 mmol, 1.0 eq.) inCH₂Cl₂ (10 mL). The ice bath was removed and the solution left to warmto room temperature before N-benzhydrylcyclooctanamine (490 mg, 1.67mmol, 1.0 eq.) was added to the stirring solution. After 5 additionalhours of stirring, (S)-binaphthol (478 mg, 1.67 mmol, 1.0 eq.) was addedto the suspension and the subsequent mixture was left to stir for anadditional 18 h. The solution was then filtered on a small pad of silicaand Celite® and rinsed with CH₂Cl₂ (˜20 mL). The resulting solution wasconcentrated under reduced pressure to afford a yellow residue. Afterflash column chromatography (Petrol: CH₂Cl₂: Et₃N; 80:19:1 SiO₂), theligand was obtained as a crystalline orange solid (350 mg, 0.61 mmol,36%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.93 (d, J=8.8 Hz, 1 H), 7.89 (d,J=8.2 Hz, 1 H), 7.85 (d, J=8.2 Hz, 1 H), 7.66-7.77 (m, 1 H), 7.17-7.53(m, 18 H), 5.70 (d, J=15.1 Hz, 1 H), 3.38 (br. dd, J=7.3, 3.2 Hz, 1 H),1.58-1.94 (m, 4 H), 1.54 (s, 1 H), 1.30-1.44 (m, 1 H), 0.99-1.26 (m, 5H), 0.81-0.98 (m, 2 H), 0.65 (br. s., 1 H). ¹³C NMR (125 MHz, CDCl₃) δppm 150.6 (d, J=6.5 Hz), 150.3, 133.2, 131.7, 131.0, 130.6, 130.0 (2 C),129.1, 129.0, 128.7 (6 C), 128.55 (3 C), 128.51, 127.5, 127.4 (2 C),127.3, 126.3 (d, J=8.3 Hz), 125.0, 124.8, 124.4 (d, J=4.6 Hz), 122.8,122.5, 122.2, 62.9, 62.7, 56.3, 26.5 (2 C), 26.1 (2 C), 25.6 (2 C). ³¹PNMR (200 MHz, CDCl₃) δ ppm 150.05 (s, 1P). HRMS (EI) m/z calcd forC₄₁H₃₇NO₂P [M−1]⁺: 606.2562, found: 606.2562. [α]²⁰ ₅₈₉=+178.27 (c 0.99,CHCl₃). IR (v_(max)/cm⁻¹): 2921, 1591, 1464, 1328, 1237, 1054, 948, 821,750.

Example 58(S)—N-benzhydryl-N-cyclohexyl)dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphos-phepin-4-amine

Triethylamine (1.57 mL, 11.30 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.19 mL, 2.26 mmol, 1.0 eq.) inCH₂Cl₂ (17 mL). The ice bath was removed and the solution left to warmto room temperature before N-benzhydrylcyclohexanamine (0.60 g, 2.26mmol, 1.0 eq.) was added to the stirring solution. After 5 additionalhours of stirring, (S)-binaphthol (0.65 g, 2.26 mmol, 1.0 eq.) was addedto the suspension and the subsequent mixture was left to stir for anadditional 18 h. The solution was then filtered on a small pad of silicaand Celite® and rinsed with CH₂Cl₂ (˜30 mL). The resulting solution wasconcentrated under reduced pressure to afford a yellow residue. Afterflash column chromatography (Petrol: CH₂Cl₂: Et₃N; 80:19:1 SiO₂), theligand was obtained as a crystalline yellow solid (0.72 g, 1.21 mmol,54%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.86-8.00 (m, 3 H), 7.78 (d, J=8.5Hz, 1 H), 7.48-7.56 (m, 2 H), 7.19-7.47 (m, 16 H), 5.77 (d, J=16.7 Hz, 1H), 3.02 (br. d, J=2.5 Hz, 1 H), 1.80 (d, J=10.1 Hz, 1 H), 1.42-1.68 (m,4 H), 1.28-1.41 (m, 2 H), 0.91 (q, J=13.1 Hz, 1 H), 0.56-0.73 (m, 2 H).¹³C NMR (125 MHz, CDCl₃) δ ppm 150.3 (d, J=6.5 Hz), 149.8, 143.5 (d,J=6.5 Hz), 143.4, 132.8, 132.6, 131.3, 130.4, 130.1, 129.3, 129.1 (d,J=2.8 Hz), 128.7 (2 C), 128.2 (4 C), 128.1, 128.0 (2 C), 127.0 (2 C),126.9 (2 C), 125.9, 125.8, 124.6, 124.3, 124.0 (d, J=5.5 Hz), 122.3,121.9, 121.7 (d, J=2.8 Hz), 60.7, 55.8, 33.8, 33.6, 26.1, 26.0, 25.3.³¹P NMR (200 MHz, CDCl₃) δ ppm 151.28 (s, 1P). HRMS (EI) m/z calcd forC₃₉H₃₄NO₂P [M]⁺: 579.2327, found: 529.2327. [α]²⁰ ₅₈₉=+219.32 (c 1.45,CHCl₃). IR (v_(max)/cm⁻¹): 2937, 2854, 1739, 1449, 1231, 948, 751.

Example 59(S)—N-benzhydryl-N-cyclopentyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphos-phepin-4-amine

Triethylamine (2.50 mL, 17.9 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.31 mL, 3.58 mmol, 1.0 eq.) inCH₂Cl₂ (26 mL). The ice bath was removed and the solution left to warmto room temperature before N-benzhydrylcyclopentanamine (0.90 g, 3.58mmol, 1.0 eq.) was added to the stirring solution. After 5 additionalhours of stirring, (S)-binaphthol (1.02 g, 3.58 mmol, 1.0 eq.) was addedto the suspension and the subsequent mixture was left to stir for anadditional 18 h. The solution was then filtered on a small pad of silicaand Celite® and rinsed with CH₂Cl₂ (˜30 mL). The resulting solution wasconcentrated under reduced pressure to afford a yellow residue. Afterflash column chromatography (Petrol: CH₂Cl₂: Et₃N; 80:19:1 SiO₂), theligand was obtained as a crystalline white solid (1.02 g, 1.77 mmol,49%). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.96 (d, J=8.8 Hz, 1 H), 7.91 (d,J=8.2 Hz, 1 H), 7.84 (d, J=7.9 Hz, 1 H), 7.62 (d, J=8.8 Hz, 1 H), 7.49(d, J=8.8 Hz, 1 H), 7.34-7.45 (m, 8 H), 7.20-7.33 (m, 8 H), 7.05 (d,J=8.5 Hz, 1 H), 5.70 (d, J=12.3 Hz, 1 H), 3.60 (sxt, J=8.7 Hz, 1 H),1.90 (d, J=8.5 Hz, 1 H), 1.81 (br. s., 1 H), 1.46-1.64 (m, 2 H),1.29-1.45 (m, 2H), 1.11-1.27 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃) δ ppm150.0 (d, J=8.3 Hz), 149.7, 143.0 (d, J=3.7 Hz), 142.7, 132.8, 132.5,131.3, 130.4, 130.2, 129.5, 129.0, 128.6 (d, J=1.8 Hz, 2 C), 128.2,128.2 (3 C), 128.1, 128.0 (3 C), 127.14, 127.11, 126.9, 125.9, 125.7,124.7, 124.3, 124.1 (d, J=5.5 Hz), 122.4 (d, J=1.8 Hz), 122.2, 121.6 (d,J=1.8 Hz), 61.4 (d, J=15.7 Hz), 57.7 (d, J=8.3 Hz), 53.4, 32.8, 32.2 (d,J=8.3 Hz), 23.6 (d, J=11.1 Hz). ³¹P NMR (200 MHz, CDCl₃) δ ppm 149.78(s, 1P). HRMS (EI) m/z calcd for C₃₈H₃₂NO₂P [M]⁺: 565.2171, found:565.2167. [α]²⁰ ₅₈₉=+207.75 (c 1.08, CHCl₃). IR (v_(max)/cm⁻¹): 2958,2360, 1739, 1590, 1463, 1230, 947, 750.

Example 60N-(9H-fluoren-9-yl)-N-isopropyldinaphtho[(R)-2,1-d:1′,2′-f][1,3,2]dioxa-phosphepin-4-amine

Triethylamine (0.84 mL, 6.0 mmol, 5.0 eq.) was added dropwise to astirred ice-cooled solution of PCl₃ (0.11 mL, 1.2 mmol, 1.0 eq.) inCH₂Cl₂ (8 mL). The ice bath was removed and the solution left to warm toroom temperature before N-isopropyl-9H-fluoren-9-amine (267 mg, 1.2mmol, 1.0 eq.) was added to the stirring solution. After 5 additionalhours of stirring, (R)-binaphthol (219 mg, 1.2 mmol, 1.0 eq.) was addedto the suspension and the subsequent mixture was left to stir for anadditional 15 h. The solution was then filtered on a small pad of silicaand Celite® and rinsed with CH₂Cl₂ (˜15 mL). The resulting solution wasconcentrated under reduced pressure to afford a yellow residue. Afterflash column chromatography (Petrol: CH₂Cl₂: Et₃N; 82:17:1 SiO₂), theligand was obtained as a crystalline white solid (364 mg, 0.67 mmol,56%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.07 (d, J=8.5 Hz, 1 H), 7.91-8.00(m, 2 H), 7.86 (d, J=7.3 Hz, 1 H), 7.81 (d, J=8.8 Hz, 1 H), 7.77 (d,J=8.2 Hz, 1 H), 7.72 (d, J=8.5 Hz, 2 H), 7.66 (d, J=6.9 Hz, 1 H), 7.60(d, J=7.6 Hz, 1 H), 7.43 (quin, J=7.3 Hz, 3 H), 7.23-7.38 (m, 6 H),7.15-7.22 (m, 1 H), 5.27 (s, 1 H), 2.38-2.54 (m, 1 H), 1.30 (d, J=6.9Hz, 3 H), 1.09-1.19 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃) δ ppm 150.3 (d,J=9.2 Hz), 150.1, 145.4, 144.5, 141.7, 140.7, 133.3, 133.1, 131.9,130.9, 130.2, 128.8, 128.7, 128.6, 128.5, 127.6, 127.6 (2 C), 127.4,127.2, 126.5, 126.4 (2 C), 126.0, 125.3, 124.9 (2 C), 124.6, 122.8 (d,J=6.5 Hz), 122.0, 120.3, 119.9, 62.5, 48.5, 26.9 (d, J=13.9 Hz), 26.7(d, J=13.9 Hz). ³¹P NMR (200 MHz, CDCl₃) δ ppm 149.07 (s, 1P). HRMS (EI)m/z calcd for C₃₆H₂₈NO₂P [M]⁺: 537.1858, found: 537.1854. [α]²⁰₅₈₉=−87.32 (c 0.99, CHCl₃). IR (v_(max)/cm⁻¹): 3064, 2966, 1771, 1231,1072, 947, 821, 747.

Example 61(R)—N-(bis(2-methoxyphenyl)methyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f]-[1,3,2]dioxaphosphepin-4-amine

Triethylamine (5.1 mL, 36.7 mmol, 5.00 eq) was added dropwise over about8 min to a stirred, cooled (water/ice bath) solution of PCl₃ (0.64 mL,7.4 mmol, 1.00 eq) in CH₂Cl₂ (50 mL). The ice bath was removed and thesolution left to warm to room temperature beforeN-(bis(3-methoxyphenyl)methyl)propan-2-amine (2.1 g, 7.4 mmol, 1.00 eq)was added to the stirring solution. (R)-Binaphthol (2.1 g, 7.4 mmol,1.00 eq) was added to the suspension after 5 hours and the subsequentmixture was left stirring overnight. The solution was then filtered overa small silica (3 mm) and Celite® (1.5 mm) pad and then washed withCH₂Cl₂. After removing the solvent in vacuo, flash column chromatographyof the yellow residue (80:19:1; Petrol/CH₂Cl₂/Et₃N; SiO₂) gavephosphoramidite(R)—N-(bis(3-methoxyphenyl)methyl)-N-isopropyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine (4.2 g, 7.0 mmol, 95%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)/ppm 7.85-7.97 (m, 4H), 7.54 (d,J=7.6 Hz, 1 H), 7.51 (d, J=8.9 Hz, 1 H), 7.36-7.47 (m, 5 H), 7.28-7.34(m, 4 H), 7.19-7.26 (m, 1 H), 6.97-7.06 (m, 2 H), 6.96 (dd, J=8.2, 1.8Hz, 2 H), 6.45 (d, J=16.3 Hz, 1 H), 3.96 (s, 3 H), 3.88 (s, 3 H), 3.58(dtd, J=13.3, 6.6, 6.6, 1.8 Hz, 1 H), 1.02 (d, J=6.7 Hz, 3 H), 0.92 (d,J=6.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ_(C)/ppm 156.7, 156.5, 150.8,150.2, 132.7, 131.6, 131.4, 131.2, 130.7, 130.5, 130.5, 130.4, 130.0,129.2, 128.3 (2 C), 128.1 (2 C), 127.1, 127.0, 125.8, 125.7, 124.5,124.1, 122.6, 122.5, 121.7, 119.9 (2 C), 110.6 (2 C), 55.4 (2 C), 49.1,48.8, 47.1, 23.0, 21.9. ³¹P NMR (160 MHz CDCl₃) δ_(P)/ppm 148.8 (d,J=15.6 Hz, 1P). HMRS (EI) m/z calcd for C₃₆H₃₀NO₂P [M]⁺: 599.2225,found: 599.2231. [α]²⁰ ₅₈₉=−89.70 (c 2.00, CHCl₃). IR (v_(max)/cm⁻¹):2972, 1589, 1463, 1232, 1053, 948, 751, 695.

Example 62

In a similar manner to the experiment described in Example 4, thecoupling of 4-phenyl-1-butene and 2-cyclohexen-1-one was evaluated inthe presence of catalytic complexes comprising, as a ligand, variouscompounds of Examples 48-61:

Catalytic complexes comprising these ligands were found to be effectiveat catalysing the above reaction, and desirable enantioselectivity wasattained. For instance, complexes comprising the compounds of Examples51-53 and 57-59 were found to provide for enantioselectivites of greaterthan 75%.

It will be understood that the present invention has been describedabove purely by way of example, and modification of detail can be madewithin the scope of the invention. Each feature disclosed in thedescription, and where appropriate the claims, may be providedindependently or in any appropriate combination.

The invention claimed is:
 1. A compound of the formula (2):

wherein: the moiety —O—C_(n)—O— is chiral and is an aliphatic oraromatic diolate, wherein said diolate is optionally substituted; eachR^(E) is the same and is an achiral substituted or unsubstituted alkylorganic group; and each R^(F) is the same and is an achiral substitutedor unsubstituted aryl organic group; or R^(F) and R^(F), together withthe carbon atom to which they are attached, form an achiral substitutedor unsubstituted cycloalkyl organic group; or a salt thereof.
 2. Thecompound according to claim 1, wherein the moiety —O—C_(n)—O— is amoiety derived from a binaphthol compound.
 3. The compound according toclaim 1, wherein each R^(E) is phenyl or naphthyl, either of which isoptionally substituted.
 4. The compound according to claim 3, whereineach R^(E) is phenyl or phenyl substituted with 1, 2, 3, 4 or 5substituents independently selected from the group consisting of C₁₋₆alkyl, halogen, trifluoromethyl and C₁₋₆ alkoxy.
 5. The compoundaccording to claim 4, wherein each R^(E) is phenyl.
 6. The compoundaccording to claim 1, wherein each R^(F) is optionally substituted C₁₋₆alkyl.
 7. The compound according to claim 6, wherein each R^(F) ismethyl.
 8. The compound according to claim 1, wherein R^(F) and R^(F),together with the carbon atom to which they are attached, form anoptionally substituted cycloalkyl group.
 9. The compound according toclaim 1, wherein each R^(E) is optionally substituted phenyl ornaphthyl; and each R^(F) is optionally substituted C₁₋₆ alkyl, or R^(F)and R^(F), together with the carbon atom to which they are attached,form an optionally substituted cycloalkyl group.
 10. The compoundaccording to claim 1, wherein each R^(E) is optionally substitutedphenyl; and each R^(F) is optionally substituted C₁₋₆ alkyl, or R^(F)and R^(F), together with the carbon atom to which they are attached,form cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any of which isoptionally substituted.
 11. The compound according to claim 1, whereineach R^(E) is phenyl or phenyl substituted with 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl, halogen,trifluoromethyl and C₁₋₆ alkoxy; and each R^(F) is methyl.
 12. Thecompound according to claim 1, wherein the compound is a compound offormula (C) or (D):


13. A catalytic complex comprising a metal and a ligand, wherein saidligand is a compound of claim
 1. 14. The catalytic complex according toclaim 13, wherein the catalytic complex further comprises a counterion.15. The catalytic complex according to claim 14, wherein the counterionis a triflimide counterion.
 16. The catalytic complex according to claim14, wherein said catalytic complex is of the formula M′L′Z′, wherein M′is a metal, L′ is a ligand which is said compound, and Z′ is acounterion.
 17. The catalytic complex according to claim 13, wherein themetal is a transition metal.
 18. A process for producing a chiralcompound in a stereoisomeric excess; wherein the process comprises:contacting a first compound comprising an alkene bond with ahydrometallating agent, wherein the first compound and thehydrometallating agent are contacted under conditions such that thefirst compound is hydrometallated by said hydrometallating agent; and(ii) contacting the hydrometallated first compound with a secondcompound, wherein the second compound comprises a conjugated π-bondsystem which is capable of undergoing a 1,4-conjugate addition reactionor a 1,6-conjugate addition reaction and which has a carbon atom at said4- or 6-position respectively, wherein the hydrometallated firstcompound and the second compound are contacted under conditions suchthat they undergo an asymmetric 1,4-conjugate addition reaction or anasymmetric 1,6-conjugate addition reaction in which a carbon atom ofsaid hydrometallated first compound binds to the carbon atom at said4-position or said 6-position of the second compound, forming astereoisomeric excess of a compound having a chiral carbon atom at said4-position or said 6-position; wherein said asymmetric 1,4-conjugateaddition reaction or said asymmetric 1,6-conjugate addition reaction isperformed in the presence of the catalytic complex of claim
 13. 19. Theprocess according to claim 18, wherein a quaternary centre is formed atthe carbon atom at said 4-position or said 6-position.
 20. The compoundaccording to claim 2, wherein the moiety —O—C_(n) —O— is a moietyderived from (R)-1,1′-bi-2-naphthol or (S)-1,1′-bi-2-naphthol.
 21. Thecompound according to claim 6, wherein each R^(F) is optionallysubstituted methyl, ethyl or propyl.